6-phenylpyridyl-2-amine derivatives

ABSTRACT

The present invention relates to certain 6-phenyi-pyridin-2-ylamine derivatives that exhibit activity as nitric oxide synthase (NOS) inhibitors, to pharmaceutical compositions containing them and to their use in the treatment and prevention of central nervous system disorders.

[0001] The present invention relates to certain 6-phenylpyridyl-2-aminederivatives that exhibit activity as nitric oxide synthase (NOS)inhibitors, to pharmaceutical compositions containing them and to theiruse in the treatment and prevention of central nervous system disorders,inflammatory disorders, septic shock and other disorders.

[0002] There are three known isoforms of NOS—an inducible form ([-NOS)and two constitutive forms referred to as, respectively, neuronal NOS(N-NOS) and endothelial NOS (E-NOS). Each of these enzymes carries outthe conversion of arginine to citrulline while producing a molecule ofnitric oxide (NO) in response to various stimuli. It is believed thatexcess nitric oxide (NO) production by NOS plays a role in the pathologyof a number of disorders and conditions in mammals. For example, NOproduced by I-NOS is thought to play a role in diseases that involvesystemic hypotension such as toxic shock and therapy with certaincytokines. It has been shown that cancer patients treated with cytokinessuch as interleukin 1 (IL-1), interleukin 2 (IL-2) or tumor necrosisfactor (TNF) suffer cytokine-induced shock and hypotension due to NOproduced from macrophages, i.e., inducible NOS (I-NOS), see Chemical &Engineering News, Dec. 20, p. 33, (1993). I-NOS inhibitors can reversethis. It is also believed that I-NOS plays a role in the pathology ofdiseases of the central nervous system such as ischemia. For example,inhibition of I-NOS has been shown to ameliorate cerebral ischemicdamage in rats, see Am. J. Physiol., 268, p.

[0003] R286 (1 995)). Suppression of adjuvant induced arthritis byselective inhibition of I-NOS is reported in Eur. J. Pharmacol., 273, p.15-24 (1995).

[0004] NO produced by N-NOS is thought to play a role in diseases suchas cerebral ischemia, pain, and opiate tolerance. For example,inhibition of N-NOS decreases infarct volume after proximal middlecerebral artery occlusion in the rat, see J. Cerebr. Blood Flow Metab.,14, p. 924-929 (1994). N-NOS inhibition has also been shown to beeffective in antinociception, as evidenced by activity in the late phaseof the formalin-induced hindpaw licking and acetic acid-inducedabdominal constriction assays, see Br. J. Pharmacol., 110, p. 219-224(1993). Finally, opioid withdrawal in rodents has been reported to bereduced by N-NOS inhibition, see Neuropsychopharmacol., 13, p. 269-293(1995).

SUMMARY OF THE INVENTION

[0005] This invention relates to compounds of the formula

[0006] and the pharmaceutically acceptable salts thereof, wherein

[0007] R¹ and R² are selected, independently, from (C₁-C₆) alkyl,tetrahydronaphthalene and aralkyl, wherein the aryl moiety of saidaralkyl is phenyl or naphthyl and the alkyl moiety is straight orbranched and contains from 1 to 6 carbon atoms, and wherein said (C₁-C₆)alkyl and said tetrahydronaphthalene and the aryl moiety of said aralkylmay optionally be substituted with from one to three substituents,preferably from zero to two substituents, that are selected,independently, from halo (e.g., chloro, fluoro, bromo, iodo), nitro,hydroxy, cyano, amino, (C₁-C₄) alkoxy, and (C₁-C₄) alkylamino;

[0008] or R¹ and R² form, together with the nitrogen to which they areattached, a piperazine, piperidine or pyrrolidine ring or an azabicyclicring containing from 6 to 14 ring members, from 1 to 3 of which arenitrogen and the rest of which are carbon, wherein examples of saidazabicyclic rings are the following

[0009] wherein R³ and R⁴ are selected from hvdrogen, (C₁-C₆)alkyl,phenyl, naphthyl, (C₁-C₆)alkyl-C(═O)—, HC(═O)—, (C₁-C₆)alkoxy-(C═O)—,phenyl-C(═O)—, naphthyl-C(═O)—, and R⁷R⁸NC(═O)— wherein R⁷ and R⁸ areselected, independently, from hydrogen and (C₁-C₆)alkyl;

[0010] R⁵ is selected from hydrogen, (C₁-C₆)alkyl, phenyl, naphthyl,phenyl-(C₁-C₆)alkyl- and naphthyl(C₁-C₆)alkyl-;

[0011] and wherein said piperazine, piperidine and pyrrolidine rings mayoptionally be substituted with one or more substituents, preferably withfrom zero to two substitnuents that are selected, independently, from(C₁-C₆)alkyl, amino, (C₁-C₆) alkylamino, [di-(C₁-C₆)alkyllamino, phenylsubstituted 5 to 6 membered heterocyclic rings containing from 1 to 4rings nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl,phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein thephenyl moieties of any of the foregoing substituents may optionally besubstituted with one or more substituents, preferably with from zero totwo substituents, that are selected, independently, from halo,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, nitro, amino, cyano, CF₃ and OCF₃;

[0012] n is 0, 1 or 2;

[0013] m is 0, 1, or 2;

[0014] each R⁸ and each R⁹ is selected, independently, from(C₁-C₄)alkyl, aryl-(C₁-C₄)alkyl wherein said aryl is selected fromphenyl and naphthyl; allyl and phenallyl;

[0015] X and Y are selected, independently, from methyl, methoxy,hydroxy and hydrogen; and

[0016] R¹⁰ is (C₁-C₆) alkyl;

[0017] with the proviso that R⁸ is absent when N is zero and R⁹ isabsent when m is zero.

[0018] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula I. The acidswhich are used to prepare the pharmaceutically acceptable acid additionsalts of the aforementioned base compounds of this invention are thosewhich form non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions, such as the hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, acetate, lactate, citrate, acid citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and Qamoate [i.e., 1,1-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0019] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof.

[0020] The term “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites.

[0021] The term “halo”, as used herein, unless otherwise indicated,includes chloro, fluoro, bromo and iodo.

[0022] Examples of preferred compounds of this invention are compoundsof the formula I, and their pharmaceutically acceptable salts, whereinNR¹R² is:

[0023] 4-phenoxycarbonylpiperazin-1-yl;

[0024] 4-(4-fluorophenylacetyl)piperazin-1-yl;

[0025] 4-phenylethylpiperazin-1-yl;

[0026] 4-phenoxymethylcarbonylpiperazin-1-yl;

[0027] 4-phenylaminocarbonylpiperazin-1-yl;

[0028] 4-benzoylmethylpiperazin-1-yl; or 4-benzylcarbonylpiperazin-1-yl.

[0029] Other preferred compounds of this invention are compounds of theformula I, and their pharmaceutically acceptable salts, wherein NR¹R² isa group of the formula

[0030] wherein NR³R⁴ is NH₂.

[0031] Other preferred compounds of this invention are compounds of theformula I, and their pharmaceutically acceptable salts, wherein NR¹R² isa group of the formula

[0032] wherein R⁵ is aralkyl, e.g., benzyl, and R⁶ is(4-fluoro)phenylacetyl.

[0033] Specific preferred compounds of the present invention include thefollowing:

[0034]1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-ethanone;

[0035]1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-methoxy-ethanone;

[0036] 1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenoxy-ethanone;

[0037](4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-cyclopentyl-methanone;

[0038]1(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;

[0039]3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.10]hex-6-ylamine;

[0040]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone;

[0041]1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone;

[0042]6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;

[0043]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanol;

[0044]{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;

[0045]6-{4-(2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine;

[0046] 6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyll-phenyl}-pyridin-2-ylamine;

[0047]6-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;

[0048](3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-dimethyl-amine;

[0049] 6-[4-(2-Amino-ethyl)-phenyl]-pyridin-2-ylamine;

[0050]6-{4-[2-(8-Aza-spiro[4.5]dec-8-yl)-ethyl]-phenyl}-pyridin-2-ylamine;

[0051]6-{4-[2-(4-1sobutyl-piperazin-1-yI)-ethyl]-phenyl}-pyridin-2-ylamine;

[0052]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide;

[0053]4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid p-tolyl-amide;

[0054]6-(4-{2-[4-(3-Phenyl-propyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine;

[0055]1-{4-(2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-chloro-phenyl)-ethanone;

[0056] 8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-benzyl-1, 3,8-triaza-spiro[4.5]decane-2, 4-dione;

[0057]N-(1-2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl)-pyrrolidin-3-yl)-2-(4-fluoro-phenyl)-acetamide;

[0058]8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-ylamine;

[0059]3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.2.1]oct-8-ylamine;

[0060]2-Amino-1-(4-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-3-phenyl-propan-1-one;

[0061]6-{4-[2-(4-Amino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;

[0062]6-{4-[2-(4-Benzhydryl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;

[0063]6-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;

[0064]6-{4-[(Cyclohexyl-methyl-amino)-methyl]-phenyl}-pyridin-2-ylamine;

[0065]6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-methoxy-phenyl}-pyridin-2-ylamine;

[0066] 6-(4-(Phenethylamino-methyl)-phenyl]-pyridin-2-ylamine;

[0067] 6-[2-Methoxy-4-(phenethylamino-methyl)-phenyl]-pyridin-2-ylamine;

[0068] 6-[4-(4-Amino-piperidin-1-ylmethyl)-phenyl}-pyridin-2-ylamine;

[0069]6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl}-pyridin-2-ylamine;

[0070] Other compounds of the formula I include:

[0071]1-(4-{2-4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;

[0072]6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-2-methoxy-phenyl}-pyridin-2-ylamine;

[0073]3-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine;

[0074]{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;

[0075]6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-methoxy-phenyl)-pyridin-2-ylamine;

[0076]6-{4-[2-(4-Amino-2-methoxy-piperidin-1-yl)-ethyl]-2-methoxy-phenyl}-pyridin-2-ylamine;

[0077]2-(4-{2-]4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide;

[0078]6-[4-(4-Amino-piperidin-1-ylmethyl)-2-methoxy-phenyl}-pyridin-2-ylamine;

[0079]1-{4-(2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;

[0080]6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-pyridin-2-ylamine;

[0081]3-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine;

[0082]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone;

[0083]1-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone;

[0084]6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-pyridin-2-ylamine;

[0085]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanol;

[0086]{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;

[0087]6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-methyl-phenyl)-pyridin-2-ylamine;

[0088] 6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-2-methyl-phenyl}-pyridin-2-ylamine;

[0089]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide;

[0090]6-[4-(4-Amino-piperidin-1-ylmethyl)-2-methyl-phenyl}-pyridin-2-ylamine;

[0091]N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-phenyl-acetamide;

[0092]N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(3-trifluoromethylphenyl)-acetamide;

[0093] N-(1{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-tolyl)-acetamide;

[0094]N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-methoxyphenyl)-acetamide;

[0095]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone;

[0096]1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone;

[0097]N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-cyclohexyl-acetamide;

[0098]2-(4-{2-4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-tolyl)-ethanone;

[0099]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-methoxyphenyl)-ethanone;

[0100]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-chlorophenyl)-ethanone;

[0101]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-fluorophenyl)-ethanone;

[0102]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-cyclohexyl-ethanone;

[0103]1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;

[0104]6-{4-[2-(4-isobutyl-piperazin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2-ylamine;

[0105]3-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine;

[0106]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone;

[0107]1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone;

[0108]6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2-ylamine;

[0109]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanol;

[0110]{2-[4-(6-Amino-pyridin-2yl)-2fluoro-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;

[0111]6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-fluoro-phenyl)-pyridin-2-ylamine;

[0112]6-{4-[2-(4-Amino-2-fluoro-piperidin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2-ylamine;

[0113]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide;

[0114]6-[4-(4-Amino-piperidin-1-ylmethyl)-2-fluoro-phenyl}-pyridin-2-ylamine;

[0115] 6-{4-[2-(4-Amino-2,6-diethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;

[0116] 6-{4-(2-(4-Amino-2,6-dibenzyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;

[0117]{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-fluoro)-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;

[0118]{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-chloro)-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;

[0119]{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-methyl)-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;and

[0120]{2-(4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-methoxy)-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine.

[0121] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a condition selected from thegroup consisting of migraine inflammatory diseases (e.g., asthma),stroke, acute and chronic pain, hypovolemic shock, traumatic shock,reperfusion injury, Crohn's disease, ulcerative colitis, septic shock,multiple sclerosis, AIDS associated dementia, neurodegenerativediseases, neuron toxicity, Alzheimer's disease, chemical dependenciesand addiction (e.g., dependencies on drugs, alcohol and nicotine),emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratorydistress syndrome (ARDS), morphine induced tolerance and withdrawalsymptoms, inflammatory bowel disease, osteoarthritis, rheumatoidarthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury,Huntington's disease, Parkinson's disease, glaucoma, maculardegeneration, diabetic neuropathy, diabetic nephropathy and cancer in amammal, including a human, comprising an amount of a compound of theformula I, or a pharmaceutically acceptable salt thereof that iseffective in treating or preventing such condition, and apharmaceutically acceptable carrier.

[0122] The present invention also relates to a method of treating orpreventing a condition selected from the group consisting of migraineinflammatory diseases (e.g., asthma), stroke, acute and chronic pain,hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease,ulcerative colitis, septic shock, multiple sclerosis, AIDS associateddementia, neurodegenerative diseases, neuron toxicity, Alzheimer'sdisease, chemical dependencies and addictions (e.g., dependencies ondrugs, alcohol and nicotine), emesis, epilepsy, anxiety, psychosis, headtrauma, adult respiratory distress syndrome (ARDS), morphine inducedtolerance and withdrawal symptoms, inflammatory bowel disease,osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy,acute spinal cord injury, Huntington's disease, Parkinson's disease,glaucoma, macular degeneration, diabetic neuropathy, diabeticnephropathy and cancer in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula I,or a pharmaceutically acceptable salt thereof, that is effective intreating or preventing such condition.

[0123] The present invention also relates to a pharmaceuticalcomposition for inhibiting nitric oxide synthase (NOS) in a mammal,including a human, comprising an NOS inhibiting effective amount of acompound of the formula I, or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier.

[0124] The present invention also relates to a method of inhibiting NOSin a mammal, including a human, comprising administering to said mammala NOS inhibiting effective amount of a compound of the formula I, or apharmaceutically acceptable salt thereof.

[0125] The present invention also relates to a pharmaceuticalcomposition for treating or preventing a condition selected from thegroup consisting of migraine, inflammatory diseases (e.g., asthma),stroke, acute and chronic pain, hypovolemic shock, traumatic shock,reperfusion injury, Crohn's disease, ulcerative colitis, septic shock,multiple sclerosis, AIDS associated dementia, neurodegenerativediseases, neuron toxicity, Alzheimer's disease, chemical dependenciesand addictions (e.g., dependencies on drugs, alcohol and nicotine),emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratorydistress syndrome (ARDS), morphine induced tolerance and withdrawalsymptoms, inflammatory bowel disease, osteoarthritis, rheumatoidarthritis ovulation, dilated cardiomyopathy, acute spinal cord injury,Huntington's disease, Parkinson's disease, glaucoma, maculardegeneration, diabetic neuropathy, diabetic nephropathy and cancer in amammal, including a human, comprising a NOS inhibiting effective amountof a compound of the formula I, or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier.

[0126] The present invention also relates to a method of treating orpreventing a condition selected from the group consisting of migraine,inflammatory diseases (e.g., asthma), stroke, acute and chronic pain,hypovolemic shock, traumatic shock, reperfusion injury, Crohn's disease,ulcerative colitis, septic shock, multiple sclerosis, AIDS associateddementia, neurodegenerative diseases, neuron toxicity, Alzheimer'sdisease, chemical dependencies and addictions (ec.a, dependencies ondrugs, alcohol or nicotine), emesis, epilepsy, anxiety, psychosis, headtrauma, adult respiratory distress syndrome (ARDS), morphine inducedtolerance and withdrawal symptoms, inflammatory bowel disease,osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy,acute spinal cord injury, Huntington's disease, Parkinson's disease,glaucoma, macular degeneration, diabetic neuropathy, diabeticnephropathy and cancer in a mammal, including a human, comprisingadministering to said mammal a NOS inhibiting effective amount of acompound of the formula II, or a pharmaceutically acceptable saltthereof.

[0127] Compounds of formula I have chiral centers and therefore mayexist in different enantiomeric and diastereomic forms. This inventionrelates to all optical isomers and all stereolsomers of compounds of theformula I and mixtures thereof, and to all pharmaceutical compositionsand methods of treatment defined above that contain or employ them,respectively.

[0128] Formulae I and II above include compounds identical to thosedepicted but for the fast that one or more hydrogen, carbon or otheratoms are replaced by isotopes thereof. Such compounds may be useful asresearch and diagnostic tools in metabolism pharmacokinetic studies andin binding assays.

DETAILED DESCRIPTION OF THE INVENTION

[0129] The compounds of the formula I may be prepared as described inthe following reaction schemes and discussion. Unless otherwiseindicated, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ and structuralformula I in the reaction schemes and discussion that follow are definedas above.

[0130] The starting materials used in the procedure of Scheme 1 areeither commercially available, known in the art or readily obtainableform known compounds by methods that will be apparent to those skilledin the art. Referring to Scheme 1, the conversion of the compound offormula II into the compound of formula III may be carried out by firstconverting the compound of formula II into the corresponding 2-aminocompound by reacting it with ammonia in a polar hydroxylic or polarnonhydroxylic solvent at a temperature of about 100° C. to about 250° C.and a pressure of about 50 to about 500 p.s.i. for about 1 to 24 hours,preferably using a stainless steel bomb. The pyrrolyl group is thenadded using hexane-2,5-dione, either neat or in a non-polar solvent suchas toluene, in the presence of an acidic catalyst such as acetic acid orhydrochloric acid, at a temperature from about room temperature to aboutthe reflux temperature, generally the latter, for about 1 to 72 hours.

[0131] The conversion of the compound of formula III formed in the abovereaction into the compound of formula IV is carried out using atransition metal mediated coupling reaction with a suitably substitutedaryl iodide or bromide. More specifically, the lithium derivative of thecompound of formula III is generated in an ethereal or hydrocarbonsolvent at a temperature from about −100° C. to about room temperature,preferably at about −78° C., using an alkyl lithium such as butyllithium, for about 10 to 120 minutes, followed by addition of acatalytic metal reagent such as zinc chloride and warming to roomtemperature to effect transmetalation. This is followed by addition ofthe aryl iodide (e.g., 1-iodo-4-(2-chloroethyl)benzene) or bromide and atransition metal, such as palladium in the form oftetrakistriphenylphosphine palladium, followed by heating to atemperature of about 30° C. to about 100° C., typically to about thereflux temperature of the solvent, for about 1 to 24 hours.

[0132] The conversion of the compound of formula IV to the desiredcompound of formula I is accomplished by first removing the pyrrolylprotecting group using, typically, hydroxylamine or hydroxylaminehydrochloride in a polar, protic solvent such as an alcohol, at atemperature of from about room temperature to about 150° C., generallyat about the reflux temperature of the solvent, for about 1 to 72 hours.This is followed by addition of the appropriate NR¹R² group bydisplacement of the chloro group with an amine of the formula HNR¹R²using a polar, aprotic or a polar, protic solvent such as an alcohol,dimethylformamide (DMF), methylisobutylketone or N-methylpyrrolidone(NMP), optionally in the presence of a catalyst such as sodium iodide,at a temperature of from about room temperature to about 200° C.,typically at about the reflux temperature of the solvent, or at about140° C. in the cases of dimethylformamide and N-methylpyrrolidone, forabout 100 hours, generally from about 12 to 24 hours.

[0133] Referring to Scheme 2, compound VI is prepared by reacting V withp-formylbenzeneboronic acid in a solvent consisting of an alcohol,preferably ethanol, optionally mixed with water of a halogenatedhydrocarbon, at a temperature from 25° C. to 150° C., for a time from 1to 24 hours, using a palladium-based catalyst, either palladium-zero orpalladium-two oxidation state, typically with phosphine ligands,preferably tetrakis-triphenylphosphine palladium. Compound VlI isprepared by reacting VI with tosylmethylisocyanide in the presence ofpotassium t-butoxide and ethanol, in an ethereal solvent such as 1,2-dimethoxyethane, at a temperature from −100° C. to 100° C., for a timefrom 1 to 24 hours. Compound VIII is prepared from VII by basichydrolysis of the nitrile using an alkali metal hydroxide in an aqueousalcohol-based solvent, such as aqueous ethanol, at a temperature from25° C. to 125° C., for a time from 30 minutes to 48 hours. Compound IXis prepared from VIII by dehydrative coupling with ammonia, a primaryamine, or a secondary amine effected by a dehydrating agent such as acarbodiimide, for example, N-ethyl-N-(dimethylaminopropyl)-carbodiimide,in a solvent from a halogenated hydrocarbon or N,N-dialkylamide, such asdimethylformamide, at a temperature from 0° C. to 100° C., for a timefrom 1 to 48 hours. Compound X is prepared from IX by deblocking usinghydroxylamine hydrochloride in an aqueous or alcoholic solvent,preferably aqueous ethanol, at a temperature from 25° C. to 1000° C.,for a time from 1 to 48 hours, and may include deblocking a protectinggroup such a the t-butoxycarbonyl group, by reaction withtrifluoroacetic acid, or a related polyhalogenated acetic acid, or agaseous hydrogen halide, such as HCl, in a halogenated hydrocarbon,ethereal solvent or ethyl acetate, at a temperature from −70° C. to 100°C., for a time from 10 minutes to 24 hours. The final compound in Scheme2, I, is prepared by reduction of X with borane, a trialkyl borane,alane, or lithium aluminum hydride in an ethereal solvent, such as ethylether or tetrahydrofuran, at a temperature from −100° C. to 100° C., fora time from 30 minutes to 24 hours, and optionally using cesium fluorideand an alkali metal or alkaline earth carbonate in an aqueous alcoholicsolvent, at a temperature from 25° C. to 125° C. for a time from 1 to 72hours.

[0134] Referring to Scheme 3, compound XI is prepared by dehydrativecoupling of N-phenethylpiperazine with 4-bromophenylacetic acid using acarbodiimide-based dehydrating reagent, such as N-ethyl,N-(dimethylaminopropyl)-carbodiimide, in a solvent such as a halogenatedhydrocarbon or dialkylamide-based solvent, such as dimethylformamide, ata temperature from 0° C. to 100° C. in a time from 1 to 48 hours.Compound XI was converted to compound XII by reduction with borane, atrialkyl borane, alane, or lithium aluminum hydride in an etherealsolvent, such as ethyl ether or tetrahydrofuran, at a temperature from−100° C. to 100° C., for a time from 30 minutes to 24 hours, andoptionally using cesium fluoride and an alkali metal or alkaline earthcarbonate in an aqueous alcoholic solvent, at a temperature from 25° C.to 125° C. for a time from 1 to 72 hours. Compound XII is then convertedto the organolithium derivative in the presence of an organolithiumreagent, such as butyl lithium, and added to 4-methyl-2-(2,5-dimethylpyrrolyl)-pyridine in an ethereal solvent, such as ethylether, at a temperature from −70° C. to 70° C. in a time from 30 minutesto 24 hours. The final compound in Scheme 3, compound I, is prepared bydeblocking using hydroxylamine hydrochloride in an aqueous or alcoholicsolvent, preferably aqueous ethanol, at a temperature from 25° C. to100° C., for a time from 1 to 48 hours.

[0135] Referring to Scheme 4, compound XIV is prepared by dehydrativecoupling of dibenzylamine with 4-bromophenylacetic acid effected by adehydrating agent such as a carbodiimide, for example,N-ethyl-N-(dimethylaminopropyl)-carbodiimide, in a solvent from ahalogenated hydrocarbon or N,N-dialkylamide, such as dimethylformamide,at a temperature from 0° C. to 100° C., for a time from 1 to 48 hours.Compound XIV is converted to compound XV by reduction with borane, atrialkyl borane, alane, or lithium aluminum hydride in an etherealsolvent, such as ethyl ether or tetrahydrofuran, at a temperature from−100° C. to 100° C., for a time from 30 minutes to 24 hours, andoptionally using cesium fluoride and an alkali metal or alkaline earthcarbonate in an aqueous alcoholic solvent, at a temperature from 25° C.to 1 25° C. for a time from 1 to 72 hours. Compound XV is then convertedto the organolithium derivative in the presence of an organolithiumreagent, such as butyl lithium, and added to 2-(2,5-dimethylpyrrolyl)-pyridine in an ethereal solvent, such as ethylether, at a temperature from −70° C. to 70° C. in a time from 30 minutesto 24 hours to provide compound XVI. Compound XVII is then prepared fromcompound XVI by hydrogenolysis with hydrogen or ammonium formate in thepresence of a noble metal catalyst, such as palladium, in an ethereal,halogenated hydrocarbon, alcoholic, or aqueous alcoholic solvent, at atemperature from 0° C. to 100° C. for a time from 30 minutes to 24hours. Compound XVIII is then prepared from compound XVII by reductiveamination with an aldehyde or ketone in the presence of aborohydride-based reagent such as sodium cyanoborohydride or sodiumtriacetoxyborohydride, in an ethereal, halogenated hydrocarbon,alcoholic, or aqueous-alcoholic solvent, at a temperature from 0° C. to100° C. for a time from 1 to 72 hours. Conversion of compound XVIII to Iby deblocking is carried out by using hydroxylamine hydrochloride in anaqueous or alcoholic solvent, preferably aqueous ethanol, at atemperature from 25° C. to 100° C., for a time from 1 to 48 hours.

[0136] Referring to Scheme 5, compound XIX is prepared by reaction ofthe known (EP 470794 A1, see Chem. Abs., 116:193935)2-bromo-5-methylanisole with an alkyl lithium, typically butyl lithium,in an ethereal or hydrocarbon solvent, at a temperature from −100° C. to0° C. for 1 minute to 24 h, followed by addition of an alkyl or arylborate ester, typically triethyl borate, at a temperature from −100° C.to 0° C., and stirred while the temperature was adjusted to 0° C. to thereflux temperature of the solvent, typically 65° C., for 1 to 48 hours.Compound XIX is converted to XX by reaction with 6-bromo-2-(2,5-dimethylpyrrolyl)pyridine and an alkali carbonate in a solventconsisting of an alcohol, preferably ethanol, optionally mixed withwater of a halogenated hydrocarbon, at a temperature from 25° C. to 150°C., for a time from 1 to 24 hours, using a palladium-based catalyst,either palladium-zero or palladium-two oxidation state, typically withphosphine ligands, preferably tetrakis-triphenylphosphine palladium.Compound XXI was prepared from XX by first deblocking usinghydroxylamine hydrochloride in an aqueous or alcoholic solvent,preferably aqueous ethanol, at a temperature from 25° C. to 100° C., fora time from 1 to 48 hours, followed by reaction withN-carbethoxyphthalimide in a hydrocarbon solvent at a temperature fromroom temperature to the reflux temperature of the solvent or 180° C.,typically 110° C., for a time from 1 to 48 hours. Conversion of compoundXXI to XXII was carried out by reaction with N-bromo succinimide in achlorinated hydrocarbon solvent, typically carbon tetrachloride, with acatalytic amount of a radical initiator such as azobisisobutyronitrile,at a temperature from room temperature to 100° C. for a time from 10minutes to 24 hours. Compound XXII was then converted to XXIII byreaction with an amine, such as phenethylamine, in a hydrocarbon,halogenated hydrocarbon, ethereal, or polar aprotic solvent, such asacetonitrile, with an alkali carbonate base, at a temperature from roomtemperature to 100° C. for a time from 10 minptes to 48 hours. CompoundXXIII was then converted to the final product in Scheme 5, I, bydeblocking using hydrazine in an alcoholic, aqueous, or etherealsolvent, at a temperature from room temperature to 150° C. for a timefrom 1 to 72 hours.

[0137] The preparation of other compounds of the formula I notspecifically described in the foregoing experimental section can beaccomplished using combinations of the reactions described above thatwill be apparent to those skilled in the art.

[0138] In each of the reactions discussed or illustrated above, pressureis not critical unless otherwise indicated. Pressures from about 0.5atmospheres to about 5 atmospheres are generally acceptable, and ambientpressure, i.e., about 1 atmosphere, is preferred as a matter ofconvenience.

[0139] The compounds of formulae I (“the active compounds of thisinvention”) which are basic in nature are capable of forming a widevariety of different salts with various inorganic and organic acids.Although such salts must be pharmaceutically acceptable foradministration to animals, it is often desirable in practice toinitially isolate a compound of the formula I from the reaction mixtureas a pharmaceutically unacceptable salt and then simply convert thelatter back to the free base compound by treatment with an alkalinereagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the active base compounds of this invention are readily prepared bytreating the base compound with a substantially equivalent amount of thechosen mineral or organic acid in an aqueous solvent medium or in asuitable organic solvent, such as methanol or ethanol. Upon carefulevaporation of the solvent, the desired solid salt is readily obtained.

[0140] The active compounds of this invention and their pharmaceuticallyacceptable salts are useful as NOS inhibitors i.e., they possess theability to inhibit the NOS enzyme in mammals, and therefore they areable to function as therapeutic agents in the treatment of theaforementioned disorders and diseases in an afflicted mammal.

[0141] The active compounds of this invention and their pharmaceuticallyacceptable salts can be administered via either the oral, parenteral ortopical routes. In general, these compounds are most desirablyadministered in dosages ranging from about 0.01 to about 250 mg per day,in single or divided doses (i.e., from 1 to 4 doses per day), althoughvariations will necessarily occur depending upon the species, weight andcondition of the subject being treated and the particular route ofadministration chosen. However, a dosage level that is in the range ofabout 0.07 mg to about 21 mg per kg of body weight per day is mostdesirably employed. Variations may nevertheless occur depending upon thespecies of animal being treated and its individual response to saidmedicament, as well as on the type of pharmaceutical formulation chosenand the time period and interval at which such administration is carriedout. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smalldoses for administration throughout the day.

[0142] The active compounds of the invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby either of the three routes previously indicated, and suchadministration may be carried out in single or multiple doses. Moreparticularly, the novel therapeutic agents of this invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,sprays, creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Moreover,oral pharmaceutical compositions can be suitably sweetened and/orflavored. In general, the therapeutically-effective compounds of thisinvention are present in such dosage forms at concentration levelsranging from about 5.0% to about 70% by weight.

[0143] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegrants such as starch (and preferably corn, potato or tapiocastarch), alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfatesand talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

[0144] For parenteral administration, solutions of an active compound ofthe present invention in either sesame or peanut oil or in aqueouspropylene glycol may be employed. The aqueous solutions should besuitably buffered (preferably pH greater than 8) if necessary and theliquid diluent first rendered isotonic. These aqueous solutions aresuitable for intravenous injection purposes. The oily solutions aresuitable for intraarticular, intramuscular and subcutaneous injectionpurposes. The preparation of all these solutions under sterileconditions is readily accomplished by standard pharmaceutical techniqueswell known to those skilled in the art.

[0145] Additionally, it is also possible to administer the activecompounds of the present invention topically when treating inflammatoryconditions of the skin and this may be done by way of creams, jellies,gels, pastes, patches, ointments and the like, in accordance withstandard pharmaceutical practice.

[0146] The ability of compounds of the formulae I to inhibit NOS may bedetermined using procedures described in the literature. The ability ofcompounds of the formulae I to inhibit endothelial NOS may be determinedby using the procedures described by Schmidt et al. in Proc. Natl. Acad.Sci. U.S.A., 88, pp. 365-369 (1991) and by Pollock et al., in Proc.Natl. Acad. Scd. U.S.A., 88, pp. 10480-10484 (1991 The ability ofcompounds of the formulae I to inhibit inducible NOS may be determinedusing the procedures described by Schmidt et al., in Proc. NatI. Acad,Sci. U.S.A., 88 pp. 365-369 (1991) and by Garvey et al. in J. Biol.Chem., 269, pp. 26669-26676 (1994). The ability of the compounds of theformula I to inhibit neuronal NOS may be determined using the proceduredescribed by Bredt and Synder in Proc. Natl. Acad. Sci. U.S.A., 87,682-685 (1990).

[0147] Of 100 compounds of the formula I that were tested, all exhibitedan IC₅₀<10 μM for inhibition of either inducible or neuronal NOS.

[0148] The present invention is illustrated by the following examptes.It will be understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (¹H NMR) and C¹³ nuclearmagnetic resonance spectra were measured for solutions indeuterochloroform (CDCl₃) or in CD₃OD or CD₃SOCD₃ and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane(TMS). The peak shapes are denoted as follows: s, singlet; d, doublet;t, triplet; q, quartet, m, multiplet, b, broad.

EXAMPLE 16-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0149] A. 2-Amino-6-bromopyridine

[0150] In a 300 mL bomb were placed 40 g(168 mmol) 2, 6-dibromopyridineand 125 mL 30% aqueous ammonium hydroxide, and the bomb sealed andheated at 170° C., 400 psi, for 3 hours. After cooling, the contentswere extracted into ethyl acetate, washed with brine and dried oversodium sulfate. Then the solvent was evaporated. The residue waschromatographed on silica gel using 2% methanol in methylene chloride aseluant to afford 19.5 g(67%) or a light yellow solid.

[0151]¹H-NMR (CDCl₃,d): 106.8, 116.8, 139.9, 158.8.

[0152] MS (%): 173/175 (parent, B⁷⁹/Br⁸¹, 100/98).

[0153] B. 2-Bromo-6-(2, 5-dimethylpyrrol-1-yl)pyridine

[0154] To a 1 L round-bottomed flask equipped with Dean-Stark trap,condenser, and nitrogen inlet were added 21.3 g(123 mmol)2-amino-6-bromopyridine, 400 mL toluene, 14.1 g(123 mmol)acetonylacetone, and 20 drops acetic acid. The reaction was refluxed 5days (tlc in 1/1:ethyl acetate/hexane, R_(f)=0.8(product), 0.5 (startingmaterial)), cooled, poured into ethyl acetate, washed with saturatedaqueous sodium bicarbonate solution and brine, dried over sodiumsulfate, and evaporated. The residue was chromatographed on silica gelusing 5% methanol in methylene chloride to afford 14.4 g(47%) of theproduct as a low-melting yellow solid.

[0155]¹H-NMR (CDCl₃, δ): 2.16 (s, 6H), 5.89 (s, 2H), 7.17 (d, J-7, 1H),7.47 (d, J=7, 1H), 7.67 (t, J=8, 1H).

[0156]¹³C-NMR (CDCl₃, δ): 13.3, 107.6, 120.3, 126.4, 128.7, 139.8,140.6, 151.9.

[0157] MS (%): 251/253 (parent, Br⁷⁹Br⁸¹, 100/98).

[0158] C. 2-(4-Iodophenyl)ethanol)

[0159] To a 500 mL 3-neck round-bottomed flask equipped with droppingfunnel and nitrogen inlet were added 20.5 g (150 mmol) 2-(4-aminophenyl)ethanol and 100 mL hot water to give a solution A solutionof 3.5 mL concentrated sulfuric acid in 10 mL water was added dropwise,and the solution cooled to 4° C. A solution of 13.5 mL concentratedsulfuric acid in 50 mL water was added dropwise while maintaining thetemperature between 0° C. and 5° C., then a solution of 13 g (188 mmol)sodium nitrite in 50 mL water was added dropwise at the sametemperature. After stirring 30 min at 0-5° C., a solution of 85 g (512mmol) potassium iodide in 100 mL water was added dropwise, and thereaction was allowed to warm to room temperature and stirred for 2 hour.The reaction was then heated to 60° C. for 30 min, cooled to roomtemperature, and extracted into ethyl acetate (2×250 mL). The ethylacetate layer was washed with aqueous sodium thiosulfate solution andbrine, dried over sodium sulfate, and evaporated. The residue waschromatographed on silica gel using 20% and 50% ethyl acetate in hexaneas eluant to afford 30.7 g (82.5%) of the product as a light yellowsolid.

[0160]¹H-NMR (CDCl, δ): 2.74 (m, 2H), 3.79 (m, 2H), 6.93 (m, 2H), 7.57(m, 2H).

[0161]¹³C-NMR (CDCl₃, δ): 38.6, 63.3, 91.7, 131.1, 137.6, 138.3.

[0162] MS(%): 247 (parent, 23).

[0163] D. 2-(4-Iodophenyl)ethylchloride

[0164] To a 500 mL round-bottomed flask equipped with dropping funnel,condenser and N₂ inlet were added 307 g (124 mmol)2-(4-iodophenyl)ethanol, 200 mL chloroform, and 10.0 mL (124 mmol)pyrdine. A solution of 13.5 mL (186 mmol) thionyl chloride in 50 mLchloroform was added dropwise over 15 min, and the reaction then heatedat reflux for 2 hr. The reaction was cooled, the solvent evaporated, andthe residue taken up in ethyl acetate, washed with 1 N hydrochloricacid, water, saturated aqueous sodium bicarbonate solution and brine,dried, and evaporated. The resulting oil was chromatographed on silicagel using 20% ethyl acetate in hexane as eluant to afford 32.6 g (99%)of the product as an oil.

[0165]¹H-NMR (CDCl₃, δ): 3.00 (t, J=7, 2H), 3.68 (t, J=7, 2H), 6.99 (m,2H), 763 (m, 2H).

[0166]¹³C-NMR (CDCl₃, δ): 38.6, 44.6, 92.3, 128.8, 130.9, 137.7.

[0167] E. 2-(2,5-Dimethylpyrrol-1-yl)-6-(4-(2-chloroethyl)phenyl)-pyridine

[0168] To a 1 L 3-neck round-bottomed flask equipped with additionfunnel and nitrogen inlet were added 10.0 g (40 mmol) 2-bromo-6-(2,5-dimethylpyrrol-1-yl)pyridine and 200 mL dry tetrahydrofuran. Thesolution was cooled at −78° C., and a 1.6 M solution of butyl lithium inhexane (25 mL, 40 mmol) was added dropwise over 10 min. The reaction wasstirred at −78° C. for 20 min, then a 1.0 M solution of zinc chloride inether (100 mL, 100 mmol) was added dropwise over 40 min keeping thetemperature at −70° C. The reaction was then allowed to warm to roomtemperature, and 11.0 g (40 mmol) 2-(4-iodophenyl)ethylchloride wasadded, followed by 200 mg tetrakistriphenylphosphine palladium. Thereaction was refluxed for 3 hours, cooled, and filtered through Celite.The filtrate was evaporated, and the residue taken up in ethyl acetate,washed with brine, dried over sodium sulfate, and evaporated. Theresidue was filtered through silica gel with methylene chloride,concentrated, and chromatographed on silica gel using 1% ethyl acetatein hexane as eluant to afford 7.3 g (59%) of the product as an oil.

[0169]¹H-NMR (CDCl₃, δ): 2.19 (s, 6H), 3.10 (t, J=7, 2H), 3.73 (t, J-7,2H), 5.91 (s, 2H), 7.12 (d, J=7, 1H), 7.32 (d, J=8, 2H), 7.72 (m, 1H),7.82 (m, 1H), 8.01 (m, 2H).

[0170]¹³C-NMR (CDCl₃, δ): 13.5, 28.9, 44.7, 106.9,118.1, 119.8, 127.1,128.7, 129.3, 137.1, 138.6, 139/.4, 151.7, 156.6.

[0171] MS (%): 311 (parent+1, 100).

[0172] F. 6-(4-(2-chloroethyl)phenyl)-pyridin-2-ylamine hydrochloride

[0173] To a 500 mL round-bottomed flask equipped with condenser andnitrogen inlet were added 9.0 g (29.0 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-chloroethyl)phenyl)-pyridine, 250 mLethanol, 50 mL water, and 10.1 g (145 mmol) hydroxylamine hydrochloride.The reaction was refluxed for 36 hours, cooled, and the solvent wasevaporated. The residue was taken up in ethyl acetate, washed withsaturated aqueous sodium bicarbonate solution and brine, dried oversodium sulfate, and evaporated. The residue was chromatographed onsilica gel using 2% methanol in methylene chloride as eluant to afford7.8 g (88%) of the product as a light brown solid.

[0174]¹H-NMR (CDCl₃, δ): 2.97 (broad s, 2H, NH₂), 3.05 (t, J=7, 2H),3.68 (t, J=7, 2H), 6.85 (m, 1H), 6.88 (m, 1H), 7.33 (m, 2H), 7.68 (6,J=7, 1H), 7.78 (m, 2H).

[0175] MS (%): 232 (parent, 60), 183 (100).

[0176] G.6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethvl]-phenyl}-pyridin-2-ylamine

[0177] To a 50 mL round-bottomed flask equipped with condenser and N₂inlet were added 20 mg (0.65 mmol)6-(4-(2-chloroethyl)phenyl)-pyridin-2-ylamine hydrochloride, 125 mg(0.98mmol) diisopropylethylamine, 208 mg (1.9 mmol) sodium carbonate, and 5mL dry dimethylformamide. The reaction was heated at reflux for 18hours, cooled, and poured into water, then extracted into ethyl acetate.The organic layer was extracted into 1 N hydrochloric acid, after whichthe aqueous layer washed with fresh ethyl acetate, basified with 1 Naqueous sodium hydroxide solution, and then extracted into ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, and evaporated. The residue was chromatographed on silica gelusing 2% and 5% methanol in methylene chloride as eluant to afford 71 mg(28%) of the product as a tan solid mp 111-113° C.

[0178]¹H-NMR (CDCl₃, δ): 2.64 (m, 6H), 2.84 (m, 2H), 4.52 (broad s, 2H),6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.45 (t, J=8,1H), 7.84 (m, 2H).

[0179]¹³C-NMR (CDCl₃, δ): 33.3, 33.6, 53.2, 60.3, 60.5, 106.9, 110.7,126.1, 126.8, 128.4, 128.7, 128.9, 137.6, 138.3, 140.3, 140.9, 156.1,158.2.

[0180] MS (%): 387 (parent+1, 100).

[0181] Anal. Calc'd for C₂₅H₃₀N₄•{fraction (1/2)}H₂O: C 75.91, H 7.90, N14.16. Found: C 76.00, H 8.01, N 14.17.

EXAMPLE 26-((2-(6-(t-butoxycarbonylamino)-3-azabicyclo[3.0]hex-3-yl)ethyl)phenyl)-pyridin-2-ylamine

[0182] The title compound was prepared using the procedure described inExample 1G using 6-(t-butoxycarbonylamino)-3-aza-bicyclo[3.1.0]hexane,in 48% yield as a brown oil.

[0183]¹H-NMR (CDCl₃, δ): 1.43 (s, 9H), 1.50 (m, 1H), 1.70 (m, 1H), 2.40(m, 1H), 2.64 (m, 1H), 2.75 (m, 1H), 3.15 (m, 1H), 4.46 (m, 1H), 6.42(d, J=8, 1H), 7.05 (d, J=7, 1H), 7.22 (m, 2H), 7.47 (t, J=8, 1H), 7.81(d, J=8, 1H).

[0184]¹³C-NMR (CDCl₃, δ): 28.4, 31.4, 35.2, 36.4, 54.5, 56.9, 79.4,106.8, 110.75, 126.7, 128.8, 137.4, 138.3, 141.1, 156.1, 158.2, 162.5.

[0185] MS (%): 395 (parent, 100).

3-2-{4-(6-Amino-pyridin-2-yl)-phenyl-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine

[0186] To a 25 mL round-bottomed flask equipped with nitrogen inlet wereadded 135 mg (0.342 mmol)6-((2-(6-(t-butoxycarbonylamino)-3-azabicyclo[3.1.0]hex-3-yl)ethyl)phenyl)-pyridin-2-ylamine,10 mL methylene chloride, and 3 mL trifluoroacetic acid. After stirring30 min at room temperature, the reaction was evaporated and the residuetriturated with tetrahydrofuran and ethyl ether to afford 195 mg (76%)of a yellowish solid, mp 187-190° C.

[0187]¹H-NMR (CDCl₃, δ): 2.33 (m, 2H), 2.95 (m, 1H), 3.10 (m, 3H), 3.47(m, 2H), 3.6-4.0 (m, 2H), 6.95 (d, J=8, 1 H), 7.13 (d, J=7, 1H), 7.49(m, 2H), 7.76 (m, 2H), 7.94 (t, J=7, 1H).

[0188]¹³C-NMR (free base in CDCl₃, δ): 25.8, 32.7, 35.2, 55.0, 57.3,106.8, 110.8, 126.7, 128.9, 137.5, 138.3, 141.0, 156.1, 158.2.

[0189] MS (%): 295 (parent+1, 100).

[0190] Anal. Calc'd for C₁₈H₂₂N₄•3(C₂HF₃O₂): C 45.29, H 3.96, N 8.80.Found: C 45.30, H 3.93, N 8.80.

EXAMPLE 31-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone

[0191] A.6-((2-(4-(t-butoxycarbonyl)piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamineThe title compound was prepared using the procedure described in Example1G using t-butoxycarbonylpiperazine in 57.5% yield withmethylisobutylketone as solvent at reflux for 5 days as a light brownsolid.

[0192]¹H-NMR (CDCl₃, δ): 1.45 (s, 9H), 2.46 (m, 4H), 2.61 (m, 2H), 2.84(m, 2H), 3.45 (m, 4H) 4.48 (broad, s, 2H), 6.42 (d, J=8, 1H), 7.05 (d,J=7, 1H), 7.25 (m, 2H), 7.47 (t, J=8, 1H), 7.84 (m, 2H).

[0193]¹³C-NMR (CDCl₃, δ): 28.4, 33.3, 53.0, 60.3, 106.9, 110.7, 126.8,128.9, 137.7, 138.3, 140.7, 154.8, 156.0, 158.2.

[0194] MS (%): 383 (parent+1, 14), 283 (70), 197 (72), 143 (70), 99(100).

[0195] B. 6-((2(piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine: Thetitle compound was prepared using the procedure described in Example 2Bin 94% yield as a light brown solid.

[0196]¹H-NMR (CDCl₃, δ): 1.69 (s, 1H), 2.49 (broad s, 4H), 2.58 (m, 2H),2.85 (m, 2H), 2.91 (m, 4H), 4.49 (broad s, 2H), 6.41 (d, J=8, 1H), 7.04(d, J=7, 1H), 7.26 (m, 2H), 7.46 (t, J=8, 1H), 7.84 (m, 2H).

[0197]¹³C-NMR (CDCl₃, δ): 33.1, 46.1, 54.5, 61.0, 106.8, 110.7, 126.8,128.9, 137.6, 138.3, 140.9, 156.1, 158.2.

[0198] MS (%): 283 (parent, 100).

[0199] C.1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone

[0200] To a 50 mL round-bottomed flask equipped with nitrogen inlet wereadded 150 mg (0.53 mmol)6-((2-(piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine, 15 mL methylenechloride, 0.070 mL (0.53 mmol) triethylamine, and 0.070 mL (0.53 mmol)phenylacetyl chloride. The reaction was stirred 1 hour at roomtemperature. The residue was chromatographed on silica gel using 2.5%methanol in methylene chloride to afford 126 mg (59%) of the product asa tan solid, mp 135-137° C.

[0201]¹H-NMR CDCl₃, δ: 2.31 (m, 2H), 2.48 (m, 2H), 2.60 (m, 2H), 2.79(m, 2H), 3.45 (m, 2H), 3.67 (m, 2H), 3.73) s, 2H), 4.53 (broad s, 2H),6.42 (d, J-8, 1H) 7.03 (d, J=7, 1H), 7.2-7.4 (m, 7H), 7.47 (t, J=8, 1H),7.82 (m, 2H).

[0202]¹3C-NMR (CDCl₃, δ): 33.1,41.0,41.7,46.0, 52.6,53.0,59.9, 107.0,110.7, 126.8, 126.9, 128.6, 128.7, 128.9, 135.1, 137.6, 138.4, 140.5,155.9, 158.2, 169.4.

[0203] MS (%): 401 (parent+1, 100).

[0204] Anal. Calc'd for C₂₅H₂₈N₄O•¼H₂O: C 74.14, H 7.04, N 13.83. Fund:C 74.48, H 7.05, N 13.86.

EXAMPLE 44-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid phenylamide

[0205] To a 50 mL round-bottomed flask equipped with nitrogen inlet wereadded 150 mg (0.53 mmol)6-((2-(piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine, 60 uL (0.53 mmol)phenylisocyanate, 10 mL 1, 2-dichloroethane, 10 mL ethyl acetate, and 64mg,(0.53 mmol) 4-dimethylaminopyridine. The reaction was stirred at roomtemperature for 14 hours, evaporated, and chromatographed on silica gelusing 5% methanol in methylene chloride as eluant to afford 205 mg (96%)of the product as a foam, mp 60° C.

[0206]¹H-NMR (CDCl₃, δ): 2.55 (m, 4H), 2.68 (m, 2H), 2.85 (m, 2H), 3.52(m, 4H), 4.49 (broad s, 2H), 6.39 (s,1H), 6.42 (d, J=8, 1H), 7.0-7.4 (m,7H), 7.48 (t, J=8, 1H), 7.86 (m, 2H).

[0207]³C-NMR (CDCl₃, δ): 33.3, 44.1, 52.8, 60.1, 106.9, 110.8, 119.9,123.1, 126.9, 128.9, 137.7, 138.4, 139.0, 140.6, 155.0, 156.0, 158.2.

[0208] MS (%): 402 (parent +1, 100).

[0209] Anal. Calc'd for C₂₄H₂₇N₅•½H₂O: C 70.22, H 6.88, N 17.06. Found:C 70.27, H 6.60, N 17.22.

EXAMPLE 51-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone

[0210] To a 50 mL round-bottomed flask equipped with nitrogen inlet wereadded 200 mg (0.71 mmol)6-((2-(piperazin-1-yl)ethyl)phenyl)-pyridin-2-ylamine,10 mL drydimethyformamide, 109 mg (0.71 mmol) 4-fluorophenylacetic acid, 204 mg(1.1 mmol) ethyl(3-dimethylaminopropyl)carbodiimide, and 0.36 mL (2.1mmol) diisopropylethylamine. The reaction was stirred at roomtemperature for 18 hours, poured into water and extracted into ethylacetate. The organic layer was extracted into 1 N hydrochloric acid, theaqueous layer washed with fresh ethyl acetate, and the aqueous layerbasified with 1 N aqueous sodium hydroxide solution and extracted intoethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and evaporated. The residue was chromatographed onsilica gel using 3% methanol in methylene chloride to afford 100 mg(34%) of the product as a tan solid, mp 143-145° C.

[0211]¹H-NMR (CDCl₃, δ): 2.34 (m, 2H), 2.46 (m, 2H), 2.60 (m, 2H), 2.79(m, 2H), 3.45 (m, 2H), 3.66 (m, 2H), 3.67 (s, 2H), 4.52 (broad s, 2H),6.41 (d, J=8, 1H), 5 6.9-7.3 (m, 6H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0212]¹³C-NMR (CDCl₃, δ): 33.2, 39.9, 41.8, 46.0, 52.7, 53.1, 59.9,106.9, 110.7, 115.4, 115.7, 126.8, 128.9, 130.2, 130.3, 130.7, 130.8,137.7, 138.3, 140.5, 155.9, 158.2, 160.1, 163.4, 169.2.

[0213] MS (%): 419 (parent+1, 100).

[0214] Anal. Calc'd for C₂₅H₂₇FN₄O: C 71.75, H 6.50, N 13.39. Found: C71.46, H 6.68, N 13.39.

EXAMPLE 6 6-{4-[2-(3,4-Dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0215] Prepared as in Example 1, using 1, 2, 3,4-tetrahydroisoquinoline, in 51% yield, mp 130-132° C.

[0216]¹H-NMR (CDCl₃, δ): 2.8-3.0 (m, 8H), 3.76 (bs, 2H), 6.39 (d, J=8,1H), 7.0-7.3 (m, 7H), 7.46 (t, J=8, 1H), 7.87 (d, J=8, 2H).

[0217]¹³C-NMR (CDCl₃, δ): 29.0, 33.6, 50.9, 55.9, 60.0, 107.0, 110.7,125.7, 126.2, 126.7, 127.0, 128.7, 129.0, 134.2, 134.5, 137.7, 138.4,140.9, 156.0, 158.4.

[0218] MS (%): 330 (parent+1, 100).

[0219] Anal. Calc'd. for C₂₂H₂₃N₃: C 80.21, H 7.04, N 12.75. Found: C80.05, H 7.11, N 12.62.

EXAMPLE 7(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-furan-2-yl-methanone

[0220] Prepared as in Example 1, using (2-furoyl)piperazine, in 51%yield, mp 152-154° C.

[0221]¹H-NMR (CDCl₃, δ): 2.55 (m, 2H), 2.65 (m, 2H), 2.82 (m, 2H), 3.81(bs, 2H), 4.55 (bs, 2H), 6.44 (m, 2H), 6.96 (m, 1H), 7.02 (d, J=8, 1H),7.23 (m, 2H), 7.45 (m, 2H), 7.83 (m, 2H).

[0222]¹³C-NMR (CDCl₃, δ): 33.2, 53.2 (broad), 60.0, 106.9, 110.6, 111.2,126.9, 128.9, 137.7, 138.3, 140.6, 143.6, 148.0, 155.9, 158.3, 159.1.

[0223] MS (%): 377 (parent+1, 100).

[0224] Anal. Calc'd. for C₂₂H₂₄N₄O₂¾H₂O: C 67.76, H 6.59, N 14.37.Found: C 67.65, H 6.25, N 14.44.

EXAMPLE 86-{4-[2-(4-m-Tolyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0225] Prepared as in Example 1, using (3-tolyl)piperazine, in 60%yield, mp 158-160° C.

[0226]¹H-NMR (CDCl₃, δ): 2.32 (s, 3H), 2.69 (m, 4H), 2.89 (m, 2H), 3.23(m, 4H), 4.52 (bs, 2H), 6.43 (d, J=8, 1H), 6.6-6.8 (m, 3H), 7.07 (d,J=8, 1H), 7.16 (m, 1H), 7.29 (m, 2H), 7.48 (t, J=8, 1H), 7.86 (m, 2H).

[0227]¹³C-NMR (CDCl₃, δ): 21.8, 33.4, 49.2, 53.3, 60.3, 106.9, 110.7,113.2, 116.9, 120.6, 126.9, 128.9, 137.7, 138.3, 138.8, 140.8, 151.4,156.0, 158.2.

[0228] MS (%): 373 (parent+1).

[0229] Anal. Calc'd. for C₂₄H₂₈N₄¼H₂O: C 76.46, H 7.62, N 14.86. Found:C 76.45, H 7.43, N 14.66.

EXAMPLE 9

[0230]6-(4-{2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0231] Prepared as in Example 1, using(3-trifluoromethylphenyl)piperazine, in 62% yield, mp 189-191° C.

[0232]¹H-NMR (CDCl₃, δ): 2.68 (m, 4H), 2.88 (m, 2H), 3.26 (m, 4H), 4.51(bs, 2H), 6.43 (d, J=8, 1H), 7.0-7.4 (m, 7H), 7.47 (t, J=8, 1H), 7.86(m, 2H).

[0233]³C-NMR (CDCl₃, δ): 33.4, 48.7, 53.0, 60.2, 106.9,110.7, 112.0,112.1, 115.7, 115.8, 118.6, 122.5, 126.2, 126.9, 128.9, 129.5, 131.2,131.6, 137.7, 138.3, 140.7, 151.4, 156.0, 158.2.

[0234] MS (%): 427 (parent+1, 41).

[0235] Anal. Calc'd. for C₂₄H₂₅F₃N₄: C 67.59, H 5.91, N 13.14. Found: C67.30, H 5.95, N 13.28.

EXAMPLE 101-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-ethanone

[0236] Prepared as in Example 1, using N-acetylpiperazine, in 47% yield,mp 201-203° C.

[0237]¹H-NMR (CDCl₃, δ): 2.08 (s, 3H), 2.49 (m, 4H), 2.62 (m, 2H), 2.82(m, 2H), 3.47 (m, 2H), 3.64 (m, 2H), 4.47 (bs, 2H), 6.43 (d, J=8, 1H),7.05 (d, J=8, 1H), 7.1-7.2 (m, 2H), 7.47 (t, J=8, 1H), 7.84 (m, 2H).

[0238]¹³C-NMR (CDCl₃, δ): 21.3, 33.3, 41.4, 46.3, 52.7, 53.3, 60.1,106.9, 110.7, 126.9, 128.9, 137.7, 138.3, 140.6, 156.0, 158.2, 168.9.

[0239] MS (%): 325 (parent+1, 100).

[0240] Anal. Calc'd. for C₁₉H₂₄N₄O: C 70.34, H 7.46, N 17.27. Found: C70.21, H 7.77, N 17.10.

EXAMPLE 111-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-methoxy-ethanone

[0241] Prepared as in Example 1, using 4-(2-methoxyacetyl)piperazine, in53% yield, mp 148-150° C.

[0242]¹H-NMR (CDCl₃, δ): 2.49 (m, 4H), 2.61 (m, 2H), 2.83 (m, 2H), 3.40(s, 3H), 3.48 (m, 2H), 3.65 (m, 2H), 4.08 (s, 2H), 4.53 (bs, 2H), 6.41(d, J=8, 1H), 7.03 (d, J=7, 1H), 7.24 (m, 2H), 7.46 (t, J=8, 1H), 7.83(m, 2H).

[0243]¹³C-NMR (CDCl₃, δ): 33.2,41.8, 44.9, 52.8, 53.4, 59.0, 60.0, 71.8,106.9, 110.7, 126.9, 128.9, 137.7, 138.3, 140.5, 155.9, 158.3, 167.4.

[0244] MS (%): 355 (parent+1, 100).

[0245] Anal. Calc'd. for C₂₀H₂₆N₄O₂: C 67.77, H 7.39, N 15.81. Found: C67.80, H 7.66, N 15.79.

EXAMPLE 12

[0246]1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenoxy-ethanone

[0247] Prepared as in Example 1, using 4-(2-phenoxyacetyl)piperazine, in57.5% yield, mp 127-130° C.

[0248]¹H-NMR (CDCl₃, δ): 2.49 (m, 4H), 2.60 (m, 2H), 2.81 (m, 2H), 3.59(m, 2H), 3.65 (m, 2H), 4.51 (bs, 2H), 4.68 (s, 2H), 6.43 (d, J =8, 1H),6.8-7.0 (m, 3H), 7.05 (d, J=8, 1H), 7.2-7.4 (m, 4H), 7.47 (t, J=8, 1H),7.83 (m, 2H).

[0249]¹³C-NMR (CDCl₃, δ): 33.2, 42.1, 45.4, 52.7, 53.3, 60.0, 67.7,106.9, 110.7, 114.6, 121.7, 126.9, 128.9, 129.6, 137.7, 138.3, 140.5,155.9, 157.8, 158.2, 166.4.

[0250] MS (%): 417 (parent+1, 100).

[0251] Anal. Calc'd. for C₂₅H₂₈N₄O₂¼H₂O: C 71.32, H 6.82, N 13.31.Found: C 71.55, H 6.93, N 13.25.

EXAMPLE 13(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-cyclopentyl-methanone

[0252] Prepared as in Example 1, using4-(cyclopentanecarbonyl)piperazine, in 53.5% yield, mp 185-187° C.

[0253]¹H-NMR (CDCl₃, δ): 1.55 (m, 2H), 1.74 (m, 2H), 1.79 (m, 4H), 2.48(m, 4H), 2.63 (m, 2H), 2.83 (m, 3H), 3.53 (m, 2H), 3.65 (m, 2H), 4.51(bs, 2H), 6.42 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.25 (m, 2H), 7.46 (t,J=8, 1H), 7.83 (m, 2H).

[0254]¹³C-NMR (CDCl₃, δ): 26.0, 30.1, 33.3, 41.0, 41.8, 45.5, 52.9,53.6, 60.1, 106.9, 110.7, 126.9, 128.9, 137.7, 138.3, 140.6, 156.0,158.2, 174.5.

[0255] MS (%): 379 (parent+1, 100).

[0256] Anal. Calc'd. for C₂₃H₃₀N₄O¾H₂O: C 70.47, H 8.10, N 14.29. Found:C 70.40, H 7.91, N 14.02.

EXAMPLE 14 6-{4-[2-(5-Methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0257] Prepared as in Example 1, using 5-methyl-2,5-diazabicyclo[3.3.1]heptane, in 29% yield, mp 132° C. (dec.) as thehydrochloride salt.

[0258] FAB MS (%): 309 (parent, 4), 279 (7), 167 (18), 149 (100), 113(19).

[0259] Anal. Calc'd. for C₁₉H₂₄N₄3HCl: C 53.34, H 6.83, N 13.10. Found:C 53.61, H 6.94, N 12.05.

EXAMPLE 15

[0260]6-(4-{2-[4-(4-Phenyl-thiazol-2-yl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0261] Prepared as in Example 1, usingN-(4-phenyl-2-thiazolyi)piperazine, in 30% yield, mp 158-161° C.

[0262]¹H-NMR (CDCl₃, δ): 2.65 (m, 4H), 2.87 (m, 2H), 3.58 (m, 6H), 4.50(bs, 2H), 6.42 (d, J=8, 1H), 6.76 (s, 1H), 7.04 (d, J=7, 1H), 7.2-7.4(m, 5H), 7.47 (d, J=8, 1H), 7.85 (m, 4H).

[0263]³C-NMR (CDCl₃, δ): 33.3, 48.4, 52.4, 60.2, 101.5, 107.0, 110.7,126.1, 126.9, 127.6, 128.5, 128.9, 129.3, 135.1, 137.6, 138.4, 140.6,151.9, 155.9, 158.2, 160.9, 171.0.

[0264] MS (%): 442 (parent+1, 100).

[0265] Anal. Calc'd. for C₂₆H₂₇N₅S¼H₂O: C 70.02, H 6.21, N 15.70. Found:C 69.92, H 6.18, N 15.31.

EXAMPLE 162-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone

[0266] Prepared as in Example 1, using N-(benzoylmethyl)piperazine, in66% yield, mp 225° C. (dec.) as the hydrochloride salt.

[0267] H-NMR (CDCl₃, δ): 2.8-3.2 (m, 10H), 3.56 (m, 2H), 3.88 (s, 2H),6.48 (m, 1H), 6.99 (m, 1H), 7.2-7.6 (m, 6H), 7.82 (m, 2H), 7.93 (m, 2H).

[0268]³C-NMR (CDCl₃, δ): 31.6, 42.4, 51.7, 52.6, 54.1, 59.2, 63.6,107.6, 110.6, 127.1, 128.0, 128.7, 129.0, 129.6, 133.5, 135.7, 137.2,138.9, 139.1, 154.8, 158.1, 170.5.

[0269] MS (%): 401 (parent+1, 100).

[0270] Anal. Calc'd. for C₂₅H₂₈N₄O 3HCl3H₂O: C 53.24, H 6.61, N 9.93.Found: C 53.39, H 6.21, N 10.06.

EXAMPLE 17

[0271]6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0272] Prepared as in Example 1, using N-isobutylpiperazine, in 44.5%yield, mp 85-88° C.

[0273]¹H-NMR (CDCl₃, δ): 0.88 (d, J=7, 6H), 1.77 (m, 1H), 2.11 (d, J=7,2H), 2.5-2.7 (m, 10H), 2.83 (m, 2H), 4.49 (bs, 2H), 6.40 (d, J=8, 1H),7.03 (d, J=7.5, 1H), 7.24 (m, 2H), 7.45 (t, J =8, 1H), 7.82 (m, 2H).

[0274]¹³C-NMR (CDCl₃, δ): 20.9, 25.3, 33.2, 53.0, 53.3, 60.2, 66.7,106.9, 110.7, 126.9, 128.9, 137.65,138.4, 140.7, 156.0, 158.3.

[0275] MS (%): 339 (parent+1, 42).

[0276] Anal. Calc'd. for C₂₁H₃₀N₄½H₂O: C 72.58, H 8.99, N 16.12. Found:C 72.98, H 9.12, N 16.44.

EXAMPLE 18 6-{4-[2-(1, 2, 3,4-Tetrahydro-naphthalen-2-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0277] Prepared as in Example 1, using 2-aminotetralin, in 18% yield, mp320-322° C. as the hydrochloride salt.

[0278]¹H-NMR (CD₃OD, δ) hydrochloride salt: 1.8-2.0 (m, 2H), 2.4-2.5 (m,4H), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 3H), 6.99 (d, J=8, 1H), 7.1-7.2 (m,5H), 7.59 (m, 2H), 7.83 (m, 2H), 7.9-8.0 (m, 1H).

[0279]¹³C-NMR (CDCl₃, δ): 15.5, 27.2, 28.4, 33.2, 56.2, 66.9, 112.0,112.9, 127.5, 127.9, 128.8, 129.8, 130.3, 131.2, 133.0, 136.0, 141.7,145.9.

[0280] MS (%): 344 (parent+1, 100).

[0281] Anal. Calc'd. for C₂₃H₂₅N₃2HCl½H₂O: C 64.94, H 6.63, N 9.88.Found: C 64.87, H 6.83, N 9.86.

EXAMPLE 19 6-(Dibenzylamino)ethyl)phenyl)-pyridin-2-ylamine

[0282] Prepared as in Example 1, using dibenzylamine, in 14% yield, mp206-208° C. as the hydrochloride salt.

[0283]¹H-NMR (CD₃OD, δ) hydrochloride salt: 2.91 (t, J=7, 2H), 3.80 (t,J=7, 2H), 4.24 (bs, 4H), 6.97 (d, J=8, 1H), 7.15 (d, J=7, 1H), 7.4-7.5(m, 12H), 7.74 (m, 2H), 7.97 (dd, J=7,8, 1H).

[0284]¹³C-NMR (CDCl₃, δ): 39.9, 52.1, 63.6, 111.8, 112.5, 128.2, 130.3,130.7, 130.9, 131.1, 131.3, 132.4, 144.8, 145.9, 148.5, 156.7.

[0285] MS (%): 309 (4), 215 (25), 198 (100), 155 (22), 135 (13),119(47), 103 (21).

[0286] Anal. Calc'd. for C₂₇H₂₇N₃3HCl: C 64.48, H 6.01, N 8.36. Found: C64.84, H 6.31, N 9.07.

EXAMPLE 206-{4-[2-(8-Aza-spiro[4.51]dec-8-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0287] Prepared as in Example 1, using 8-Aza-spiro[4.5]decane, in 63%yield, mp 130-132° C.

[0288]¹H-NMR (CDCl₃, δ): 1.3-1.7 (m, 12H), 2.47 (bs, 4H), 2.59 (m, 2H),2.86 (m, 2H), 4.49 (bs, 2H), 6.42 (d, J=8, 1H), 7.04 (d, J=7.5, 1H),7.2-7.3 (m, 2H), 7.46 (t, J=8, 1H), 7.83 (m, 2H).

[0289]¹³C-NMR (CDCl₃, δ): 24.3, 33.5, 37.5, 38.0, 40.7, 51.5, 60.8,106.8, 110.7, 126.8, 128.9, 137.6, 138.3, 141.1, 156.1, 158.2.

[0290] MS (%): 336 (parent+1, 79).

[0291] Anal. Calc'd. for C₂₂H₂₉N₃¼H₂O: C 77.72, H 8.75, N 12.36. Found:C 77.74, H 8.74, N 12.41.

EXAMPLE 21

[0292]6-{4-[2-(4-Dimethylamino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0293] Prepared as in Example 1, using 4-(N,N-dimethylamino)piperidine,in 60% yield, mp 174-176° C.

[0294]¹H-NMR (CDCl₃, δ): 1.5-1.6 (m, 2H), 1.8 (m, 2H), 2.0 (m, 2H), 2.29(s, 6H), 2.60 (m, 2H), 2.80 (m, 2H), 3.15 (m, 2H), 3.4-3.5 (m, 1H), 4.51(bs, 2H, NH), 6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.24 (m, 2H), 7.46(t, J=8, 1H), 7.82 (m, 2H).

[0295]¹³C-NMR (CDCl₃, δ): 28.1, 33.6, 41.5, 53.1, 60.4, 62.3, 106.9,110.7, 126.8, 128.9, 137.6, 138.3, 141.0, 156.1, 158.2.

[0296] MS (%): 325 (parent+1, 100), 280 (45), 197 (65).

[0297] Anal. Calc'd. for C₂₃H₂₅N₃½H₂O: C 72.03, H 8.77, N 1 6.80. Found:C 72.09, H 8.57, N 16.86.

EXAMPLE 22 6-{4-[2-(1,3-Dihydro-isoindol-2-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0298] Prepared as in Example 1, using dihydroisoindole, in 19% yield,mp 140-143° C.

[0299]¹H-NMR (CDCl₃, δ): 2.97 (m, 4H), 4.00 (bs, 4H), 4.51 (bs, 2H),NH), 6.42 (d, J=8, 1H), 7.06 (d, J=8, 1H), 7.20 (m, 4H), 7.32 (m, 2H),7.47 (t, J=8, 1H), 7.86 (m, 2H).

[0300]¹³C-NMR (CDCl₃, δ): 35.5, 57.8, 59.2, 106.9, 110.8, 122.3, 1 26.7,1 26.9, 128.9, 137.7, 138.3, 139.9, 140.8, 156.1, 158.2.

[0301] MS (%): 316 (parent+1, 92), 197 (43), 132 (100).

[0302] Anal. Calc'd. for C₂₁H₂₁N₃½H₂O: C 77.75, H 6.84, N 12.95. Found:C 78.03, H 6.78, N 12.58.

EXAMPLE 23

[0303]2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide

[0304] Prepared as in Example 1, using4-(N-isopropylacetamido)piperazine, in 78% yield, mp 163-165° C.

[0305]¹H-NMR (CDCl₃, δ): 1.14 (d, J6, 6H), 2.55 (m, 8H), 2.6 (m, 2H),2.75 (m, 2H), 2.96 (s, 2H), 4.07 (hp, J =6, 1H), 4.52 (bs, 2H, NH), 6.42(d, J=8, 1H), 6.92 (m, 1H), 7.03 (d, J=7, 1H), 7.24 (m, 2H), 7.46 (t,J=8, 1H), 7.82 (m, 2H).

[0306]¹³C-NMR (CDCl₃, δ): 22.8, 33.4, 40.7, 53.2, 53.4, 60.2, 61.6,106.9, 110.7, 126.9, 128.9, 137.7, 138.3, 140.7, 156.0, 158.2, 169.1.

[0307] MS (%): 382 (parent+1, 100), 198 (75).

[0308] Anal. Calc'd. for C₂₂H₃₁N₅O: C 69.26, H 8.19, N 18.36. Found: C68.97, H 8.36, N 18.58.

EXAMPLE 24

[0309](4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-aceticacidethyl ester

[0310] Prepared as in Example 1, using4-(N-carboethoxymethyl)piperazine, in 16% yield, as a low-melting sold.

[0311]¹H-NMR (CDCl₃, δ): 1.26 (t, J=7, 3H),2.5-2.7 (m,10H),2.83(m,2H),3.20 (s, 2H), 4.17 (q, J=7, 2H), 4.49 (bs, 2H), 6.41 (d, J=8,1H), 7.04 (d, J=7, 1H), 7.25 (m, 2H), 7.46 (t, J=7, 1H), 7.82 (m, 2H).

[0312]¹³C-NMR (CDCl₃, δ): 14.25, 33.3, 52.9, 53.0, 59.6, 60.2, 60.6,106.9, 110.7, 126.8, 128.9, 137.6, 138.3, 140.8, 156.0, 158.2, 170.3.

[0313] IR (cm.⁻¹, KBr): 1740 (C=O).

[0314] MS (%): 369 (parent+1, 100), 197 (35), 185 (70), 119 (38).

[0315] HRMS (%): 369.23070 (parent+1, 100, calculated 369.22905).

EXAMPLE 25(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-phenyl-methanone

[0316] Prepared as in Example 1, using (N-benzoyl)piperazine, in 43%yield, mp 125-127° C.

[0317]¹H-NMR (CDCl₃, δ): 2.4 (m, 2H), 2.5-2.7 (m, 4H), 2.85 (m, 2H), 3.5(m, 2H), 3.8 (m, 2H), 4.53 (bs, 2H), NH), 6.41 (d, J=8, 1H), 7.03 (d,J=7, 1H), 7.24 (m, 2H), 7.38 (m, 5H), 7.45 (t, J=8, 1H), 7.83 (m, 2H).

[0318]¹³C-NMR (CDCl₃, δ): 33.2, 60.1, 106.9, 110.7, 126.9, 127.1, 128.5,128.9, 129.7, 135.8, 137.7, 138.3, 140.5, 155.9, 158.3, 170.3.

[0319] MS (%): 387 (parent+1, 92), 203 (35), 105 (100).

[0320] Anal. Calc'd. for C₂₄H₂₆N₄O¼H₂O: C 73.72, H 6.83, N 14.33. Found:C 73.96, H 6.88, N 14.39.

EXAMPLE 266-{4-[2-(3-Phenyl-pyrrolidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0321] Prepared as in Example 1, using 3-phenylpyrrolidine, in 54%yield, mp 100° C. (dec.) as the hydrochloride salt.

[0322]¹H-NMR as the hydrochloride salt (MeOD, δ): 2.2-2.6 (m, 2H),3.2-3.4 (m, 5H), 3.5-3.7 (m, 2H), 3.7-4.0 (m, 2H), 6.99 (d, J=8, 1H),7.17 (d, J=7, 1H), 7.3-7.5 (m, 5H), 7.59 (m, 2H), 7.83 (m, 2H), 7.97 (t,J=8, 1H).

[0323]¹³C-NMR (CDCl₃, δ): (the aliphatic and some of the aromaticcarbons are doubled, possibly due to restricted rotation) 31.9, 32.7,32.8, 34.2, 55.0, 56.5, 56.9, 57.5, 60.6, 60.9, 111.9, 112.9, 128.4,128.6, 128.7,128.9, 130.0, 131.2, 131.9, 139.8, 140.8, 141.6, 145.9,147.8, 156.8.

[0324] MS (%): 344 (parent+1, 100), 197 (26), 160 (40).

[0325] Anal. Calc'd. for C₂₃H₂₅N₃2HCl{fraction (5/4)}H₂O: C 62.94, H6.77, N 9.57. Found: C 62.90, H 6.93, N 9.46.

EXAMPLE 27

[0326]6-(4-{2-[4-(1-Phenyl-1H-tetrazol-5-yl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0327] Prepared as in Example 1, using4-(N-phenyltetrazol-5-yl)piperazine, in 50% yield, mp 212-214° C.

[0328]¹H-NMR (CDCl₃, δ): 2.55 (m, 4H), 2.64 (m, 2H), 2.80 (m, 2H), 3.28(m, 4H), 4.52 (bs, 2H, NH), 6.42 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.23(m, 2H), 7.4-7.6 (m, 6H), 7.81 (m, 2H).

[0329]¹³C-NMR (CDCl₃, δ): 33.2, 48.7, 52.1, 60.0, 107.0, 110.7, 123.7,123.8, 126.9),128.9, 129.7, 129.9, 130.1, 135.0, 137.7, 138.4, 140.5,155.9, 157.5, 158.2, 160.8.

[0330] MS (%): 427 (parent+1, 100), 197 (85).

[0331] Anal. Calc'd. for C₂₄H₂₆N₈.½H₂O: C 66.19, H 6.25, N 25.73. Found:C 66.03, H 6.24, N 25.88.

EXAMPLE 28 2-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]ethyl}-1, 2, 3,4-tetrahydro-isoquinoline-3-carboxylic acid

[0332] Prepared as in Example 1, using 3-carboxy(1, 2, 3,4-tetrahydroisoquinoline), in 17% yield, mp 110° C. (dec.) as thehydrochloride salt.

[0333]¹H-NMR (CDCl₃, δ): 2.9-3.1 (m, 6H), 3.7 (m,1H), 4.4 (m, 2H), 4.54(bs, 2H, NH), 6.43 (d, J=8, 1H), 7.0-7.2 (m, 4H), 7.05 (d, J=7, 1H),7.28 (m, 2H), 7.47 (t, J=8, 1H), 7.86 (m, 2H).

[0334]¹³C-NMR (CDCl₃, δ): 31.6, 34.8, 47.2, 55.9, 65.3, 107.0, 110.7,126.1, 126.2, 127.0, 129.1, 133.1, 134.8, 138.1, 138.2, 138.4, 155.8,158.3, 173.1.

[0335] MS (%): 374 (parent+1, 81), 197 (100).

[0336] Anal. Calc'd. for C₂₃H₂₃N₃O₂HCl¼H₂O: C 60.13, H 6.47, N 9.15.Found: C 60.54, H 6.07, N 8.78.

EXAMPLE 294-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid (4-chloro-phenyl)-amide

[0337] Prepared as in Example 4, using 4-chlorophenylisocyanate, in75.5% yield, mp 160-162° C.

[0338]¹H-NMR (CDCl₃, δ): 2.49 (m, 4H), 2.60 (m, 2H), 2.80 (m, 2H), 3.47(m, 4H), 4.69 (bs, 2H, NH), 6.40 (d, J=8, 1H), 6.96 (d, J=7, 1H),7.1-7.4 (m, 6H), 7.44 (t, J=8, 1H), 7.73 (m, 2H).

[0339]³C-NMR (CDCl₃, δ): 33.0, 43.7, 52 7, 60.0, 107.3, 110.9, 121.4,121.5, 127.0, 127.9, 128.7, 128.9, 137.7, 137.8, 138.6, 140.4, 155.3,155.9, 158.4.

[0340] MS (%): 436 (parent+1, 24), 283 (27), 155 950), 119 (100).

[0341] Anal. Calc'd. for C₂₄H₂₆N₅OCl: C 66.12, H 6.01, N 16.06. Found: C65.92, H 6.21, N 16.18.

EXAMPLE 304-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid p-tolyl-amide

[0342] Prepared as in Example 4, using 4-methylphenylisocyanate, in 79%yield, Fpp 160-162° C.

[0343]¹H-NMR (CDCl₃, δ): 2.28 (s, 3H), 2.52 (m, 4H), 2.64 (m, 2H), 2.82(m, 2H), 3.49 (m, 4H), 4.52 (bs, 2H, NH), 6.42 (d, J=8, 1H), 6.44 (m,1H), 7.0-7.1 and 7.2-7.4 (m, 6H), 7.47 (d, J=8, 1H), 7.84 (m, 2H).

[0344]¹³C-NMR (CDCl₃, δ): 20.8, 33.25, 44.1, 52.8, 60.1, 107.0, 110.7,120.3, 126.9, 128.9, 129.4, 136.4, 137.7, 138.4, 140.6, 155.2, 155.9,158.2.

[0345] MS (%): 416 (parent+1, 71), 283 (100), 2332(73), 197 (70), 119(53), 99 (66).

[0346] Anal. Calc'd. for C₂₅H₂₉N₅O: C 72.26, H 7.03, N 16.85. Found: C72.07, H 7.13, N 16.99.

EXAMPLE 314-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid (4-methoxy-phenyl)-amide

[0347] Prepared as in Example 4, using 4-methoxyphenylisocyanate, in 80%yield, mp 182-184° C.

[0348]¹H-NMR (CDCl₃, δ): 2.53 (m, 4H), 2.66 (m, 2H), 2.83 (m, 2H), 3.49(m, 4H), 3.75 (s, 3H), 4.57 (bs, 2H, NH), 6.42 (d, J=8, 1H), 6.80 (m,2H), 7.02 (d, J=7, 1H), 7.1-7.3 (m, 4H), 7.47 (t, J=8, 1H), 7.80 (m,2H).

[0349]¹³C-NMR (CDCl₃, δ): 33.1, 44.0, 52.7, 52.8, 60.1, 107.1, 110.8,114.1, 122.4, 122.6, 126.9, 128.9, 131.9, 137.7, 138.5, 140.5, 155.7,155.9, 158.3.

[0350] MS (%): 432 (parent+1, 15.5), 283 (20), 155 (50), 119 (100), 103(47).

[0351] Anal. Calc'd. for C₂₅H₂₉N₅O₂¼H₂O: C 68.86, H 6.82, N 16.06.Found: C 68.80, H 6.80, N 16.20.

EXAMPLE 324-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid cyclohexylamide

[0352] Prepared as in Example 4, using cyclohexylisocyanate, in 79%yield, mp 180-182° C.

[0353]¹H-NMR (CDCl₃, δ): 1.1 (m, 3H), 1.3 (m, 2H), 1.8 (m, 3H), 2.0 (m,2H), 2.48 (m, 4H), 2.63 (m, 2H), 2.82 (m, 2H), 3.36 (m, 4H), 3.63 (m,1H), 4.30 (d, J=5, 1H, NH), 4.54 (bs, 2H, NH), 6.41 (d, J=8, 1H), 7.03(d, J=8, 1H), 7.25 (m, 2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0354]¹³C-NMR (CDCl₃, δ): 25.1, 25.7, 33.3, 34.0, 43.7, 49.4, 52.8,60.2, 106.9, 110.7, 126.9, 137.6, 138.4, 140.6, 155.9, 157.0, 158.2.

[0355] MS (%): 408 (parent+1, 55), 283 (100), 224 (50), 197 (60), 119(44).

[0356] Anal. Calc'd. for C₂₄H₃₃N₅O¼H₂O: C 69.96, H 8.19, N 17.00. Found:C 70.13, H 8.32, N 17.19.

EXAMPLE 334-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid phenyl ester

[0357] Prepared as in Example 4, using phenyl chloroformate, in 19%yield, mp 102-104° C.

[0358]¹H-NMR (CDCl₃, δ): 2.57 (m, 4H), 2.69 (m, 2H), 2.83 (m, 2H),3.6-3.8 (m, 4H), 4.52 (bs, 2H, NH), 6.42 (d, J=8, 1H), 7.1-7.4 (m, 7H),7.48 (t, J=8, 1H), 20 7.85 (m, 2H).

[0359]¹³C-NMR (CDCl₃, δ): 33.3, 44.0, 44.5, 52.5, 53.0, 60.2, 107.0,110.7, 121.7, 125.3, 127.0, 128.9, 129.3, 137.7, 138.4,140.6,151.4,153.7, 155.95, 158.2.

[0360] MS (%): 403 (parent+1, 100), 219 (90), 197 (77).

[0361] Anal. Calc'd. for C₂₄H₂₆N₄O₂: C 71.62, H 6.51, N 13.92. Found: C71.23, H 6.55, N 14.01.

EXAMPLE 34 6-(4-{2-[4-(1-Phenyl-1H-imidazol-2-yl)-piperazin-1-yl]-ethyl-phenyi)-pyridin-2-ylamine

[0362] Prepared as in Example 1, using(N-phenylimidazol-2-yl)piperazine, in 63% yield, mp 140-142° C.

[0363]¹H-NMR (CDCl₃, δ): 2.49 (m, 4H), 2.60 (m, 2H), 2.76 (m, 2H), 3.07(m, 4H), 4.55 (bs, 2H, NH), 6.39 (d, J=8, 1H), 6.84 (s, 2H), 7.01 (d,J=7, 1H), 7.22 (m, 2H), 7.3-7.6 (m, 6H), 7.80 (m, 2H).

[0364]¹³C-NMR (CDCl₃, δ): 33.3, 49.6, 52.7, 60.6,106.9, 110.6, 118,3,123.8, 125.4, 126.8, 127.2, 128.9, 129.4, 137.6, 138.3, 140.75, 151.3,156.0, 158.3.

[0365] MS (%): 425 (parent+1, 100),241 (33), 197 (40),184 (32),172 (55),160 (38).

[0366] Anal. Calc'd. for C₂₆H₂₈N₆¼H₂O: C 72.79, H 6.70, N 19.59. Found:C 72.63, H 6.56, N 19.66.

EXAMPLE 35 6-[4-(2-Phenethylamino-ethyl)-phenyl]-pyridin-2-ylamine

[0367] Prepared as in Example 1, using benzylamine, in 38% yield, mp212-215° C. as the hydrochloride salt.

[0368]¹H-NMR (CD₃OD, δ) hydrochloride salt: 3.04 (m, 2H), 3.14 (m, 2H),3.30 (m, 4H), 6.99 (d, J=8, 1H), 7.17 (d, J=7, 1H), 7.2-7.4 (m, 5H),7.55 (m, 2H), 7.83 (m, 2H), 7.97 (m, 1H).

[0369]³C-NMR (CDCl₃, δ): 33.0,33.4, 111.9, 112.9, 128.3, 128.9, 129.8,130.0, 131.1, 132.0, 137.8, 141.7, 145.9, 147.9, 156.8.

[0370] MS (%): 318.3009 (parent+1, 100, calculated 318.19702).

[0371] Anal. Calc'd. for C₂₁H₂₃N₃2HClH₂O: C 61.77, H 6.66, N 10.29.Found: C 61.49, H 6.67, N 10.35.

EXAMPLE 361-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-3-phenyl-urea

[0372] Prepared from the final compound in Example 2, usingphenylisocyanate, in 67% yield, mp 192-194° C.

[0373]¹H-NMR (CDCl₃, δ): 1.59 (m, 2H), 2.52 (m, 2H), 2.65 (m, 2H), 2.78(m, 2H), 3.30 (m, 2H), 3.34 (m, 1H), 6.50 (d, J=8, 1H), 6.97 (m, 2H),7.2-7.4 (m, 6H), 7.48 (t, J=8, 1H), 7.74 (m, 2H).

[0374]¹³C-NMR (CDCl₃, δ): 25.8, 31.8, 35.9, 55.9, 58.5, 108.5, 111.2,120.4, 123.6, 128.0,129.8, 129.9, 139,1, 139.7, 140.7, 142.1, 157.2,158.9, 160.9.

[0375] MS (%): 414 (parent+1, 100), 226 (40), 149 (81), 127 (63).

[0376] Anal. Calc'd. for C₂₅H₂₇N₅O: C 72.61, H 6.58, N 16.94. Found: C72.34, H 6.24, N 17.00.

EXAMPLE 37(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-dimethyl-amine

[0377] Prepared from the final compound in Example 2, using formaldehydein formic acid at 80° C. for 2.5 hr, in 56.5% yield, as an amorphoussolid.

[0378]¹H-NMR (CDCl₃, δ): 1.47 (m, 2H), 1.89 (m, 1H), 2.31 (s, 6H), 2.41(m, 2H), 2.66 (m, 2H), 2.74 (m, 2H), 3.08 (m, 2H), 4.52 (bs, 2H, NH),6.42 (d, J=8, 1H), 7.05 (d, J=7, 2H), 7.24 (m, 2H), 7.47 (t, J=8, 1H),7.83 (m, 2H).

[0379]³C-NMR (CDCl₃, δ): 24.8, 35.3, 45.1, 48.3, 55.0, 57.4, 106.8,110.7, 459.7, 128.8, 137.5, 138.3, 141.1, 156.1, 158.2.

[0380] MS (%): 323 (parent+1, 7), 167 (35), 149 (100), 113 (37).

[0381] Anal. Calc'd. for C₂₀H₂₆N3HClH₂O: C 53.40, H 6.45, N 12.45.Found: C 53.44, H 7.03, N 12.32.

EXAMPLE 38N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-2-(4-fluoro-phenyl)-acetamide

[0382] Prepared from the final compound in Example 2, using4-fluorophenylacetic acid coupling mediated by N-ethyl,N-(3-dimethylaminopropyl)carbodiimide, in 38% yield, mp 161-163° C.

[0383]¹H-NMR (CDCl₃, δ): 1.42 (m, 2H), 2.36 (m, 2H), 2.63 (m, 2H), 2.70(m, 2H), 2.88 (m, 1H), 3.15 (m, 2H), 3.45 (s, 2H), 4.51 (bs, 2H, NH),5.49 (bs, 1H, NH), 6.42 (d, J=8, 1H), 7.0-7.3 (m, 7H), 7.46 (t, J=8,1H), 7.80 (m, 2H).

[0384]¹³C-NMR (CDCl₃, δ): 24.3, 30.5, 35.1, 42.8, 54.4, 56.7, 106.9,110.7, 115.6, 115.9, 126.7, 128.8, 130.8, 130.9, 137.4, 138.3, 141.0,156.0, 158.2, 160.4, 163.7, 171.5.

[0385] MS (%): 431 (parent+1, 100), 226 (33), 197 (60 ), 109 (60).

[0386] Anal. Calc'd. for C₂₆H₂₇FN₄O½H₂O: C 71.05, H 6.42, N 12.75.Found: C 71.14, H 6.53, N 12.60.

EXAMPLE 396-(4-{2-[4-(3-Phenyl-allyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0387] Prepared as in Example 1, using (3-phenyl-allyl)-piperazine, in67% yield, mp 249-255° C. (hydrochloride salt).

[0388]¹H-NMR as the hydrochloride salt (CDCl₃/MeOD, δ): 3.27 (m, 2H),3.56 (m, 2H), 3.7-4.0 (m, 8H), 4.08 (d, J=7, 2H), 6.34 (m, 2H), 6.95 (m,2H), 7.11 (d, J=7, 1H), 7.33 (m, 2H), 7.51 (m, 3H), 7.79 (m, 2H), 7.93(dd, J=7,8, 1H).

[0389]³C-NMR (CDCl₃, δ): 27.1, 31.1, 57.0, 58.1, 59.9, 112.0, 113.2,116.5, 128.4, 1218.5, 128.8, 129.0, 131.9, 136.4, 141.0, 143.2,145.8,147.8, 150.3, 156.8.

[0390] MS (%): 399 (parent+1, 54), 149 (77), 119 (93), 117 (100).

[0391] Anal. Calc'd. for C₂₈H₃₀N₄3HCl½H₂O: C 60.41, H 6.63, N 10.84.Found: C 60.7;9, H 6.65, N 10.67.

EXAMPLE 406-(4-{2-[4-(3-Phenyl-propyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0392] Prepared as in Example 1, using (3-phenyi-propyl)-piperazine, in64% yield, mp 258-264° C. (hydrochloride salt).

[0393]¹H-NMR (CDCl₃, δ): 1.83 (m, J=8, 2H), 2.54 (m, 2H), 2.6-2.8 (m,12H), 2.83 (m, 2H), 4.47 (bs, 2H, NH), 6.42 (d, J=8, 1H), 7.05 (d, J=7,1H), 7.1-7.3 (m, 7H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0394]¹³C-NMR (CDCl₃, δ): 28.6, 33.3, 33.7, 53.2, 58,0, 60.3, 65.8,106.8, 110.7, 125.8, 126.8, 128.3, 128.4, 128.9, 137.6, 138.3, 140.9,142.1, 156.1, 158.2.

[0395] MS (%): 401 (parent+1, 10), 167 (21), 149 (100), 113 (24).

[0396] Anal. Calc'd. for C₂₆H₃₂N₄3HCl{fraction (5/2)}H₂O: C 56.27, H7.26, N 10.10. Found: C 56.35, H 7.47, N 9.72.

EXAMPLE 414-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1carboxylicacid (3, 4-dimethyl-phenyl)-amide

[0397] Prepared as in Example 4, using 3, 4-dimethylphenylisocyanate, in90% yield, mp 122-125° C.

[0398]¹H-NMR (CDCl₃, δ): 2.15 (s, 3H), 2.18 (s, 3H), 2.47 (m, 4H), 2.65(m, 2H), 2.85 (m, 2H), 3.55 (m, 4H), 4.55 (bs, 2H, NH), 6.35 (s, 1H),6.42 (d, J=8, 1H), 7.0-7.3 (m, 5H), 7.47 (t, J=8, 1H), 7.82 (m, 2H).

[0399]¹³C-NMR (CDCl₃, δ): 19.0, 19.9, 33.2, 44.1, 52.8, 60.1, 104.0,110.7, 117.7, 121.7, 126.9, 128.9, 129., 131.4, 136.6, 137.0, 137.6,138.4, 140.6, 155.2, 155.9, 158.2.

[0400] MS (%): 430 (parent+1, 41), 283 (100), 246 (58), 197 (81), 99(76).

[0401] Anal. Calc'd. for C₂₆H₃₁N₅O: C 72.70, H 7.27, N 16.30. Found: C72.51, H 7.33, N 16.06.

EXAMPLE 42

[0402]1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-chloro-phenyl)-ethanone

[0403] Prepared as in Example 5, using 4-chlorophenylacetic acid, in 38%yield, mp 205° C. (dec., hydrochloride salt).

[0404]¹H-NMR (CDCl₃, δ): 2.37 (m, 2H), 2.49 (m, 2H), 2.59 (m, 2H), 2.62(m, 2H), 3.45 (m, 2H), 3.6 (m, 2H), 3.67 (s, 2H), 4.86 (bs, 2H, NH),6.42 (d, J=8, 1H), 7.01 (d, J=7, 1H), 7.1-7.3 (m, 6H), 7.47 (dd, J=7, 8,1H), 7.79 (m, 2H).

[0405]¹³C-NMR (CDCl₃, δ): 33.1, 40.0, 41.7, 45.9, 52.6, 53.0, 59.8,107.2, 110.7, 127.0, 128.5, 128.8, 130.0, 130.8, 122.7, 133.5, 137.3,138.6, 140.5, 155.6, 158,2, 169.0.

[0406] MS (%): 435 (parent+1, 100), 251 (49), 197 (61), 119 (62).

[0407] Anal. Calc'd. for C₂₅H₂₇N₄ClO¼H₂O: C 68.33, H 6.31, N 12.75.Found: C 68.59, H 6.13, N 12.53.

EXAMPLE 43 8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-benzyl-1, 3,8-triaza-spiro[4.5]decane-2, 4-dione

[0408] Prepared as in Example 1, using3-benzyl-1,3,8-triaza-spiro[4.5]decane-2, 4-dione (prepared as describedin WO 95/12577 (1995)), in 42% yield, mp 190° C. (dec., as thehydrochloride salt).

[0409]¹H-NMR (CDCl₃, δ): 1.62 (m, 2H), 2.11 (m, 2H), 2.23 (m, 2H), 2.63(m, 2H), 2.82 (m, 2H), 2.95 (m, 2H), 4.50 (bs, 2H, NH), 4.63 (s, 2H),6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.2-7.4 (m, 7H), 7.46 (dd, J=7,8,1H), 7.83 (m, 2H).

[0410]¹³C-NMR (CDCl₃, δ): 33.2, 33.4, 42.1, 49.0, 60.1, 60.2, 106.9,110.7, 126.9, 127.8, 128.3, 128.7, 128.9, 136.1, 167.7, 138.4, 140.7,155.9, 156.8, 158.2, 176.0.

[0411] MS (%): 456 (parent+1, 100), 272 (81), 197 (79), 119 (35).

[0412] Anal. Calc'd. for C₂₇H₂₉N₅O₂½H₂O (analyzed as the free base): C69.81, H 6.51, N 15.07. Found: C 69.94, H 6.52, N 15.00.

EXAMPLE 443-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.2.1]oct-8-ylamine

[0413] Prepared as in Example 2, using 3-aza-bicyclo[3.2.1]oct-8-ylaminet-butylcarbamate followed by removal of the t-butylcarbamate group, in83% yield, mp 235° C. (dec., as the hydrochloride salt).

[0414]¹H-NMR (CDCl₃, δ): 1.69 (m, 4H), 1.82 (m, 2H), 2.59 (m, 6H), 2.75(m, 2H), 2.97 (m, 1H), 4.53 (bs, 2H, NH), 6.39 (d, J=8, 1H), 7.03 (d,J=7, 1H), 7.24 (m, 2H), 7.43 (dd, J=7, 8, 1H), 7.82 (m, 2H).

[0415]¹³C-NMR (CDCl₃, δ): 26.9, 33.2, 39.2, 52.1, 54.1, 59.7, 106.8,110.65, 126.6, 128.9, 139.3, 138.3, 141.6, 156.1, 158.2.

[0416] MS (%): 323 (parent+1, 10), 167 (24), 149 (100), 113 (27).

[0417] Anal. Calc'd. for C₂₀H₂₈N₄HCl{fraction (7/4)}H₂OCH₂Cl₂: C 53.06,H 6.89, N 11.79. Found: C 53.35, H 7.07, N 11.79.

EXAMPLE 454-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid m-tolyl-amide

[0418] Prepared as in Example 3, using 3-tolylisocyanate, in 85% yield,mp 88-94° C.

[0419]¹H-NMR (CDCl₃, δ): 2.30 (s, 3H), 2.52 (m, 4H), 2.64 (m, 2H), 2.83(m, 2H), 3.50 (m, 4H), 4.54 (bs, 2H, NH), 6.42 (d, J=8, 1H), 6.48 (s,1H), 6.83 (d, J=7, 1H), 7.04 (d, J=7, 1H), 7.1-7.3 (m, 4H), 7.47 (t,J=8, 1H), 7.83 (m, 2H).

[0420]¹³C-NMR (CDCl₃, δ): 21.5, 33.2, 44.1, 52.8, 60.1, 107.0, 110.7,117.1, 120.8, 123.9, 126.9, 128.7, 128.9, 137.7, 138.4, 138.7, 138.9,140.6, 155.1, 155.9, 158.2.

[0421] MS (%): 416 (parent+1, 33), 283 (100), 232 (60), 197 (95).

[0422] Anal. Calc'd. for C₂₅H₂₉N₅O: C 72.26, H 7.03, N 16.85. Found: C72.08, H 7.08, N 16.74.

EXAMPLE 46(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-phenethyl-amine

[0423] Prepared using the final product of Example 2, by reaction withphenylacetaldehyde and sodium cyanoborohydride in methanol, in 41%yield, mp 165° C. (dec., as the hydrochloride salt.

[0424]¹H-NMR (CDCl₃, δ): 1.43 (m, 2H), 2.4 (m, 3H), 2.6 (m, 2H), 2.8 (m,4H), 2.92 (m, 2H), 3.09 (m, 2H), 4.51 (bs, 2H, NH), 6.41 (d, J=8, 1H),7.04 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.43 (t, J=8, 1H), 7.82 (m, 2H).

[0425]¹³C-NMR (CDCl₃, δ): 24.4, 35.0, 36.1, 39.0, 50.6, 55.0, 57.3,106.9, 110.7, 126.1, 126.8, 128.5, 128.7, 128.9, 137.6, 138.35, 140.0,140.7, 156.0, 158.2.

[0426] HRMS (%): Calc'd. for C₂₆H₃₀N₄: 399.2549. Found: 399.2534.

EXAMPLE 474-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid benzylamide

[0427] Prepared as in Example 3, using benzylisocyanate, in 60% yield,mp 172-1 75° C.

[0428]¹H-NMR (MeOD, CDCl₃, δ); 2.48 (m, 4H), 2.63 (m, 2H), 2.80 (m, 2H),3.39 (m, 4H), 4.37 (s, 2H), 4.61 (bs for NH₂, partly exchanged), 5.03(m, NH, partly exchanged), 6.41 (d, J=8, 1H), 6.99 (d, J=7, 1H), 7.1-7.3(m, 7H), 7.45 (t, J =8, 1H), 7.76 (m, 2H).

[0429]¹³C-NMR (CDCl₃, δ): 33.1, 43.6, 44.8, 52.8, 60.1, 107.1, 110.8,126.9, 127.3, 127.7, 128.6, 128.9, 137.7, 138.5, 139.3, 140.5, 155.9,157.7, 158.3.

[0430] MS (%): 416 (parent+1, 60), 283 (100), 232 (56), 197 (80), 99(70).

[0431] Anal. Calc'd. for C₂₅H₂₉N₅O¼H₂O: C 71.49, H 7.28, N 16.67. Found:C 71.45, H 7.06, N 16.67.

EXAMPLE 486-[4-(2-{4-[1-(4-Fluoro-phenyl)-1H-tetrazol-5-yl]-piperazin-1-yl}-ethyl)-phenyl]-pyridin-2-ylamine

[0432] Prepared as in Example 1, using[(4-fluoro-phenyl)-1H-tetrazol-5-yl]piperazine, in 20% yield, mp185-187° C.

[0433]¹H-NMR (CDCl₃, δ): 2.58 (m, 4H), 2.67 (m, 2H), 2.81 (m, 2H), 3.28(m, 4H), 4.51 (bs, 2H, NH), 6.45 (d, J=8, 1H), 7.06 (d, J=7, 1H),7.2-7.3 (m, 4H), 7.49 (t, J=8, 1H), 7.60 (m, 2H), 7.85 (m, 2H).

[0434]¹³C-NMR (CDCl₃, δ): 33.2, 48.7, 52.1, 60.0, 106.9, 110.7, 116.8,117.1, 125.8, 125.9, 126.9, 128.9, 131.0, 137.7, 138.4, 140.4, 155.9,157.6, 158.2, 161.1, 164.5.

[0435] MS (%): 445 (parent+1, 85), 197 (80), 119 (100), 103 (84).

[0436] Anal. Calc'd. for C₂₄H₂₅N₈F: C 64.85, H 5.67, N 25.21. Found: C64.63, H 5.75, N 25.36.

EXAMPLE 496-(4-{2-[4-cis-(4-Phenyl-cyclohexyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0437] Prepared as in Example 1, usingcis-(4-phenyl-cyclohexyl)-piperazine, in 46% yield, mp 127-130° C.

[0438]¹H-NMR (CDCl₃, δ): 1.58 (m, 4H), 1.95 (m, 4H), 2.27 (m, 1H),2.6-2.8 (m, 10H), 2.83 (m, 2H), 4.50 (bs, 2H, NH), 6.42 (d, J=8, 1H),7.06 (d, J=7, 1H), 7.2-7.3 (m, 7H), 7.47 (t, J=8, 1H), 7.85 (m, 2H).

[0439]¹³C-NMR (CDCl₃, δ): 28.0, 28.4, 33.4, 42.8, 49.8, 53.8,59.1, 60.5,106.9, 110.71,125.7, 126.8, 127.1, 128.2, 128.9, 129.2, 137.6, 138.3,141.0, 147.1, 156.1, 158.2.

[0440] MS (%): 441 (parent+1, 59), 257 (75), 197 (40), 91 (100).

[0441] Anal. Calc'd. for C₂₉H₃₆N₄O¼H₂O: C 78.25, H 8.27, N 12.59. Found:C 78.30, H 8.22, N 12.70.

EXAMPLE 506-(4-{2-[4-trans-(4-Phenyl-cyclohexyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0442] Prepared as in Example 1, usingtrans-(4-phenyl-cyclohexyl)-piperazine, in 54% yield, mp 178-180° C.

[0443]¹H-NMR (CDCl₃, δ): 1.49 (m, 4H), 2.03 (m, 4H), 2.47 (m, 2H), 2.65(m, 8H), 2.85 (m, 2H),4.50 (bs, 2H, NH), 6.42 (d, J=8, 1H), 7.05 (d,J=7, 1H), 7.1-7.2 (m, 7H), 7.47 (t, J=8, 1H), 7.84 (m, 2H).

[0444]¹³C-NMR (CDCl₃, δ): 28.9,33.3,33.5, 44.1, 49.1,53.5, 60.4, 63.3,106.9, 110.7, 126.0, 126.8, 126.9, 128.3, 128.9, 137.6, 138.3, 140.9,146.9, 156.0, 158.2.

[0445] MS (%): 441 (parent+1, 89), 257 (90), 197 (40), 91 (100).

[0446] Anal. Calc'd. for C₂₉H₃₆N₄O¼H₂O: C 78.25, H 8.27, N 12.59. Found:C 77.98, H 8.25, N 12.60.

EXAMPLE 51(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-(3-phenyl-propyl)-aminehydrochloride salt

[0447] Prepared from the final compound in Example 2, using3-phenylpropionaldehyde via reductive amination using sodiumcyanoborohydride in methanol, in 27% yield, mp 160-163° C. as thehydrochloride salt from 1, 2-dichloroethane.

[0448]¹H-NMR (CDCl₃, δ): 1.44 (m, 2H), 1.83 (qn, 2H), 2.43 (m, 3H),2.6-2.8 (m, 8H), 3.09 (m, 2H), 4.54 (bs; 2H, NH), 6.43 (d, J=8, 1H),7.07 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.48 (t, J=8, 1H), 7.85 (m, 2H).

[0449]³C-NMR (CDCl₃, δ): 24.4, 31.5, 33.6,35.2,39.0,49.1, 55.0, 57.3,106.8, 110.7, 125.8, 126.7, 128.3, 128.4, 128.9, 137.5, 138.3, 141.0,142.1, 156.1, 158.2.

[0450] MS (%): 413 (parent+1, 70), 226 (73), 197 (66), 91 (100).

[0451] Anal. Calc'd. for C₂₇H₃₂N₄2HCl.2H₂O½C₂H₄Cl₂: C 58.90, H 7.(06, N9.81. Found: C 59.19, H 7.18, N 9.46.

EXAMPLE 522-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamino)-acetamide

[0452] Prepared from the final compound in Example 2, usingiodoacetamide, in 39.5% yield, mp 140° C. (dec.).

[0453]¹H-NMR (CDCl₃, δ): 1.51 (m, 2H), 2.41 (m, 1H), 2.50 (m, 2H), 2.65(m, 2H), 2.75 (m, 2H), 3.05 (m, 2H), 3.25 (s, 2H), 6.49 (d, J=8, 1H),6.96 (d, J=7, 1H), 7.24 (m, 2H), 7.48 (dd, J=7, 8, 1H), 7.74 (m, 2H).

[0454]¹³C-NMR (CDCl₃, δ): 25.3, 35.7, 40.6, 56.1, 58.6, 60.1, 108.5,111.1, 128.0, 129.8, 139.2, 139.7, 141.9, 157,1, 161.0, 177.0.

[0455] HRMS (%): 352 (parent+1, 43), 155 (47), 119 (100), 103 (54).

EXAMPLE 536-[4-(2-{4-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-ethyl)-phenyl]-pyridin-2-ylamine

[0456] Prepared as in Example 1, using (4-fluoro)phenethyl-piperazine,in 35% yield, mp 165-167° C.

[0457]¹H-NMR (CDCl₃, δ): 2.5-2.7 (m, 12H), 2.7-2.9 (m, 4H), 4.51 (bs,2H, NH), 6.42 (d, J=8, 1H), 6.95 (m, 2H), 7.05 (d, J=8, 1H), 7.14 (m,2H), 7.25 (m, 2H), 7.47 (t, J=8, 1H), 7.83 (m, 2H).

[0458]¹³C-NMR (CDCl₃, δ): 32.8, 33.3, 53.1, 60.3, 60.5, 106.9, 110.7,115.0, 115.3, 126.8, 128.9, 130.0, 130.1, 135.9, 136.0, 137.6, 138.3,140.9, 156.1, 158,2, 159.8, 163.0.

[0459] MS (%): 405 (parent+1, 92), 221 (100), 197 (53), 123 (75).

[0460] Anal. Calc'd. for C₂₅H₂₉FN₄¼H₂O: C 72.61, H 7.31, N 13.55. Found:C 72.74, H 7.05, N 13.22.

EXAMPLE 546-(4-{2-[4-(1-Methyl-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0461] Prepared as in Example 1, using1-methyl-2-phenyl-ethyl-piperazine, in 30% yield, mp 252-256° C. as thehydrochloride salt.

[0462]¹H-NMR (CDCl₃, δ): 0.95 (d, J=6, 3H), 2.41 (m, 1H), 2.5-2.7 (m,10H), 2.83 (m, 3H), 3.04 (m, 1H), 4.54 (bs, 2H, NH), 6.41 (d, J=8, 1H),7.04 (d, J=7, 1H), 7.1-7.3 (m, 7H), 7.46 (t, J=8, 1H), 7.84 (m, 2H).

[0463]¹³C-NMR (CDCl₃, δ): 14.4, 33.4, 39.3, 48.3, 53.6, 60.4, 61.3,106.9, 110.7, 125.8, 126.9, 127.0, 128.2, 128.9, 129.3, 137.6, 138.3,140,6, 140.9, 156.1, 158.3.

[0464] MS (%): 401 (parent+1, 64), 309 (35), 217 (40), 197 (34), 91(100).

[0465] Anal. Calc'd. for C₂₆H₃₂N₄3HCl.H₂O: C 59.15, H 7.06, N 10.61.Found: C 59.07, H 7.22, N 10.46.

EXAMPLE 55 6-(4-{2-[4-(1, 2, 3,4-Tetrahydro-naphthalen-2-yl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0466] Prepared as in Example 1, using 4-(1, 2, 3,4-tetrahydro-naphthalen-2-yl)-piperazine, in 33% yield, mp>220° C. asthe hydrochloride salt.

[0467]¹H-NMR (CDCl₃, δ): 1.65 (m, 1H), 2.15 (m, 1H), 2.6-3.0 (m, 17H),4.52 (bs, 2H, NH), 6.41 (d, J=8, 1H), 7.09 (m, 5H), 7.26 (m, 2H), 7.46(t, J=8, 1H), 7.84 (m, 2H).

[0468]¹³C-NMR (CDCl₃, δ): 26.1, 29.4,32.0,33.3,49.1, 53.5,60.3,60.4,106.9, 110.7, 125.7, 125.8, 126.9, 128.5, 128.9, 129.5, 135.9, 136.4,137.6, 138.3, 140.9, 156.1, 158.2.

[0469] MS (%): 413 (parent+1, 30), 229 (65), 197 (30), 131 (100).

[0470] Anal. Calc'd. for C₂₇H₃₂N₄3HCl: C 62.13, H 6.76, N 10.73. Found:C 62.44, H 7.11, N 10.49.

EXAMPLE 56N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-fluoro-phenyl)-acetamide

[0471] Prepared from(1-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-amine,using 4-fluorophenylacetic acid coupling mediated by N-ethyl,N-(3-dimethylaminopropyl)carbodiimide, in 55% yield, mp 90° C. (dec.).

[0472]¹H-NMR (CDCl₃, δ): 1.54 (m, 2H), 2.24 (m, 3H), 2.53 (m, 1H), 2.72(m, 2H), 2.79 (m, 2H), 2.98 (m, 1H), 4.5 (m, 2H), 6.19 (m, 1H), 6.40 (d,J=8, 1H), 7.02 (m, 3H), 7.20 (m, 4H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0473]¹³C-NMR (CDCl₃, δ): 32.1, 34.6, 42.7, 48.6, 52.8, 57.2, 60.6,107.0, 110.7, 115.5, 115.7, 126.9, 128.8, 130.8, 130.9, 137.8, 138.4,140.2, 155.8, 158.3, 160.8, 163.2, 170.2.

[0474] MS (%): 419 (parent+1,43), 391 (38),167 (40),149 (100),119(46),113 (73).

[0475] HRMS: Calc'd. for C₂₅H₂₈N₄OF: 419.2247. Found: 419.2266.

EXAMPLE 57 8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-phenethyl-1,3, 8-triaza-spiro[4.5]decane-2, 4-dione

[0476] Prepared as in Example 1, using 3-phenethyl-1, 3,8-triaza-spiro[4.5]decane-2, 4-dione, in 45% yield, mp 176-180° C. asthe hydrochloride salt.

[0477]¹H-NMR (CDCl₃, δ): 1.51 (m, 2H), 2.02 (m, 2H), 2.23 (m, 2H), 2.63(m, 2H), 2.82 (m, 2H), 2.92 (m, 4H), 3.73 (t, J=7, 2H), 4.54 (bs, 2H,NH), 6.42 (d, J=8, 1H), 7.05 (m, 2H), 7.2-7.3 (m, 5H), 7.47 (t, J=8,1H), 7.83 (m, 2H).

[0478]³C-NMR (CDCl₃, δ): 33.2, 33.3, 33.8, 39.5, 49.0, 59.7, 60.1,106.9, 110.7, 126.6, 126.9, 128.5, 128.9, 129.0, 137.7, 138.4, 140.7,156.0, 156.8, 158.3, 176.1.

[0479] MS (%): 470 (parent+1, 70), 360 (67), 340 (100), 338 (75), 332(55).

[0480] Anal. Calc'd. for C₂₈H₃₁N₅O₂½H₂O: C 70.27, H 6.74, N 14.63.Found: C 70.16, H 6.65, N 14.85.

EXAMPLE 588-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-ylamine

[0481] Prepared as in Example 1, using 8-aza-bicyclo[3.2.1]oct-3-ylamineas the t-butyl carbamate, followed by deprotection using trifluoroaceticacid, in 67% yield, mp>300° C. as the hydrochloride salt.

[0482]¹H-NMR (CDCl₃, δ): 1.45 (m, 4H), 1.54 (m, 2H), 1.68 (m, 2H), 1.91(m, 2H), 2.63 (m, 2H), 2.78 (m, 2H), 2.93 (m, 1H), 3.29 (m, 2H), 4.50(bs, 2H, NH), 6.39 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.24 (m, 2H), 7.45(t, J=8, 1H), 7.81 (m, 2H).

[0483]¹³C-NMR (CDCl₃, δ): 26.9, 35.6, 41.2, 43.0, 53.3, 58.8, 106.8,110.7, 126.7, 128.9, 137.5, 138.3, 141.1, 156.0, 158.2.

[0484] MS (%): 323 (parent+1, 23), 197 (25), 149 (36), 109 (57), 95(100).

[0485] Anal. Calc'd. for C₂₀H₂₆N₄HCl{fraction (3/2)}H₂OCH₂Cl₂: C 53.57,H 6.85, N 11.90. Found: C 53.90, H 7.09, N 12.14.

EXAMPLE 594-Amino-1{-2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperidine-4-carboxylicacid benzylamide

[0486] Prepared as in Example 1, using 4-amino-piperidine-4-carboxylicacid benzyiamide, mp>240 ° C. (dec.) as the hydrochloride salt.

[0487]¹H-NMR (CDCl₃, δ): 1.47 (m, 2H), 2.36 (m, 4H), 2.64 (m, 2H), 2.87(m, 2H), 2.92 (,m 2H), 4.42 (d, J=6, 2H), 4.47 (s, 2H), 6.42 (d, J=8,1H), 7.05 (d, J=7, 1H), 7.2-7.4 (m, 7H), 7.47 (t, J=8, 1H), 7.83 (m,2H), 8.02 (bs, 1H, NH).

[0488]¹³C-NMR (CDCl₃, δ): 33.1, 34.8, 43.2, 48.9, 55.1, 60.3, 107.1,110.9, 126.9, 127.3, 127.6, 128.6, 128.9, 137.7, 138.5, 140.5, 156.0,158.3, 177.0.

[0489] MS (%): 430 (parent+1, 100), 197 (47), 133 962).

[0490] Anal. Calc'd. for C₂₆H₃₁N₅OHCl{fraction (5/4)}H₂OCH₂Cl₂: C 56.55,H 6.42, N 1 2.21. Found: C 56.88, H 6.84, N 12.09.

EXAMPLE 606-(4-{2-[4-(2-Amino-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0491] Prepared as in Example 1, using (2-amino-ethyl)-piperazine as thet-butylcarbamate, followed by deprotection using trifluoroacetic acid inmethylene chloride, in 90% yield, as a hygroscopic solid as thetrifluoroacetate salt.

[0492]¹H-NMR (CDCl₃, δ): 1.93 (m, 2H), 2.3-2.5 (m, 14H), 2.81 (m, 2H),4.50 (bs, 2H, NH), 6.40 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.23 (m, 2H),7.45 (t, J=8, 1H), 7.81 (m, 2H).

[0493]¹³C-NMR (CDCl₃, δ): 33.3,53.2, 60.4,106.9, 110.7,126.8,128.9,137.6, 138.3, 140.9, 156.0, 158.2.

[0494] MS (%): 326 (parent+1, 8), 167 (25), 149 (100), 133 (45), 119(28), 113 (25).

[0495] HRMS. Calc'd. for C₁₉H₂₇N₅: 326.2345. Found: 326.2340.

EXAMPLE 612-Amino-1-(4-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-3-phenyl-propan-1-one

[0496] Prepared from the title compound in Example 3B, using t-BOCphenylalanine coupling mediated by N-ethyl,N-(3-dimethylaminopropyl)carbodiimide, in 68% yield, followed bydeprotection using trifluoroacetic acid in methylene chloride in 78%yield, mp 230° C. (dec.) as the hydrochloride salt from ethyl ether.

[0497]¹H-NMR (CDCl₃, δ): 1.89 (m, 1H), 2.31 (m, 2H), 2.50 (m, 3H), 2.74(m, 3H), 2.90 (m, 1H), 3.10 (m, 1H), 3.31 (m, 1H), 3.5-3.7 (m, 2H), 3.94(m, 1H), 4.59 (bs, 2H, NH), 6.39 (d, J=8, 1H), 7.02 (d, J=7, 1H),7.1-7.3 (m, 7H), 7.44 (t, J=8, 1H), 7.82 (m, 2H).

[0498]¹³C-NMR (CDCl₃, δ): 33.1, 41.9, 45.2, 52.5, 52.8, 59.9, 107.0,110.6, 126.9, 128.6, 128.8, 129.4, 137.6, 137.7, 138.3, 140.5, 155.8,158.3, 173.0.

[0499] MS (%): 430 (parent+1, 23), 167 (26), 149 (100), 133 (72), 113(25).

[0500] HRMS: Calc'd. for C₂₆H₃₁N₅O3HCl{fraction (5/4)}H₂O: C 56.19, H6.99, N 11.70. Found: C 56.55, H 6.73, N 11.32.

EXAMPLE 62(2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

[0501] Prepared as in Example 1, using(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine, mp 260° C. (dec.) as thehydrochloride salt.

[0502]¹H-NMR (CDCl₃, δ): 1.45 (m, 3H), 1.53 (m, 2H), 1.72 (m, 2H), 1.97(m, 2H), 2.7-2.9 (m, 4H), 3.18 (m, 2H), 3.54 (s, 2H), 4.49 (bs, 2H, NH),6.41 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.2-7.4 (m, 7H), 7.46 (t, J=8,1H), 7.83 (m, 2H).

[0503]¹³C-NMR (CDCl₃, δ): 27.0, 36.5, 38.3, 48.1, 48.9, 55.5, 58.5,106.9, 110.8, 126.6, 126.9,128.1, 128.5, 128.9, 137.7, 138.3, 140.3,140.7, 156.0, 158.2.

[0504] MS (%): 413 (parent+1, 6), 200 (40), 133 (28), 91 (100).

[0505] Anal. Calc'd. for C₂₇H₃₂N₄3HClH₂O: C 60.06, H 6.91, N 10.38.Found: C 60.33, H 6.82, N 10.39.

EXAMPLE 631-{2-[4-6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperidin-4-yl)-3-phenyl-urea

[0506] Prepared as in Example 1, using 4-(phenylureido)-piperidine,mp>280° C. as the hydrochloride salt.

[0507]¹H-NMR (CDCl₃, δ): 1.41 (m, 2H), 1.93 (m, 2H), 2.17 (m, 2H), 2.585(m, 2H), 2.79 (m, 2H), 2.92 (m, 2H), 3.60 (m, 1H), 6.39 (d, J=8, 1H),6.92 (m, 2H), 7.2-7.4 (m, 7H), 7.42 (t, J=8, 1H), 7.69 (m, 2H).

[0508]¹³C-NMR (CDCl₃, MeOD, δ): 31.9, 32.8, 46.2, 52.4, .60.1, 107.3,110.9, 119.0, 122.4, 127.0, 128.8, 137.8, 138.6,139.3, 140.0, 155.6,155.9, 158.5.

[0509] MS (%): 416 (parent+1, 78), 323 (52), 232 (50), 197 (100), 133(82), 119 (79), 103 (69).

[0510] Anal. Calc'd. for C₂₅H₂₉N₅O2HCl½H₂O¾CH₂Cl₂: C 55.11, H 6.02, N12.48. Found: C 55.34, H 6.05, N 12.14.

EXAMPLE 641-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperidin-4-yl)-3-benzyl-urea

[0511] Prepared as in Example 1, using 4-(benzylureido)-piperidine, in24% yield, mp 1 20° C. (dec.) as the hydrochloride salt.

[0512]¹H-NMR (CDCl₃, δ): 1.42 (m, 2H), 1.93 (m, 2H), 2.16 (m, 2H), 2.58(m, 2H), 2.7-2.9 (m, 4H), 3.60 (m, 1H), 4.32 (d, J=5, 2H), 4.48 (bs, 2H,NH), 4.90 (m, 1H), 6.41 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.1-7.3 (m,7H), 7.46 (t, J=8, 1H), 7.81 (m, 2H).

[0513]¹³C-NMR (CDCl₃, δ): 32.7, 33.4, 44.5, 47.1, 52.3, 60.2, 106.9,110.8, 126.9, 127.3, 127.5, 128.6, .128.9, 137.7, 138.6, 139.2, 140.6,156.0, 157.5, 158.2.

[0514] MS (%): 430 (parent+1, 10), 155 (50), 135 (28), 119 (100), 103(55).

[0515] Anal. Calc'd. for C₂₆H₃₁N₅O2HClH₂O: C 60.00, H 6.78, N 13.45.Found: C 60.23, H 6.57, N 13.29.

EXAMPLE 65N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperidin-4-yl)-2-(4-fluoro-phenyl)-acetamide

[0516] Prepared as in Example 1, using4-((4-fluorophenyl)acetamido)-piperidine, in 35% yield, mp 170° C.(dec.) as the hydrochloride salt.

[0517]¹H-NMR (CDCl₃, δ): 1.37 (m, 2H), 1.88 (m, 2H), 2.14 (m, 2H), 2.59(m, 2H), 2.77 (m, 2H), 2.83 (m, 2H), 3.50 (s, 2H), 3.79 (m, 1H), 4.46(bs, 2H, NH), 5.23 (d, J=7, 1H), 6.42 (d, J=8, 1H), 7.02 (m, 3H),7.2-7.3 (m, 5H), 7.46 (dd, J=7,8, 1H), 7.81 (m, 2H).

[0518]¹³C-NMR (CDCl₃, δ): 32.0, 33.5, 43.0, 46.5, 52.2, 60.2, 106.9,110.7, 115.7, 115.95, 126.8, 128.9, 130.8, 130.9, 137.6, 138.3, 140.7,156.0, 158.2, 170.0.

[0519] MS (%): 433 (parent+1, 70), 155 (48), 119 (100), 103 (61).

[0520] Anal. Calc'd. for C₂₆H₂₉N₄OF2HCl¾H₂O: C 60.17, H 6.31, N 10.80.Found: C 60.56, H 6.24, N 10.75.

EXAMPLE 66{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(8-aza-bicyclo[3.2.1]oct-3-yl)-amine

[0521] Prepared as in Example 1, usingN-benzyl-(8-aza-bicyclo[3.2.1]oct-3-yl)-amine followed by debenzylationusing ammonium formate and 10% palladium-on-carbon in ethanol, in 71%yield, mp 170° C. (dec.) as the hydrochloride salt.

[0522]¹H-NMR (CDCl₃, δ): 1.24 (m, 2H), 1.58 (m, 2H), 1.7-1.9 (m, 4H),2.7-2.9 (m, 4H), 3.54 (m, 2H), 4.10 (m, 1H), 4.49 (bs, 2H, NH), 6.41 (d,J=8, 1H), 7.04 (d, J=7, 1H), 7.2-7.3 (m, 2H), 7.46 (m, 1H), 7.82 (m,2H).

[0523]¹³C-NMR (CDCl₃, δ): 29.1, 36.4, 40.7, 47.9, 19.0, 54.2, 106.9,110.8, 126.9, 128.9, 137.7, 138.4, 140.5, 156.0, 158.2.

[0524] MS (%): 323 (parent+1, 66), 199 (55), 133 (81), 110 (100).

[0525] Anal. Calc'd. for C₂₀H₂₆N₄2HCl2H₂O¼CH₂Cl₂: C 53.73, H 7.24, N12.38. Found: C 53.48, H 7.23, N 12.04.

EXAMPLE 676-{4-[2-(4-Amino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0526] Prepared as in Example 1, using4-(t-butoxycarbonylamino)-piperidine followed by deblocking withtrifluoroacetic acid in methylene chloride at room temperature, in 100%yield, mp 190-195° C. as the trifluoroacetate salt.

[0527]¹H-NMR (TFA salt, CDCl₃, δ): 1.99 (m, 2H), 2.28 (m, 2H), 3.17 (m,4H), 3.41 (m, 2H), 3.50 (m, 1H), 3.78 (m, 2H), 6.96 (d, J=8, 1H), 7.14(d, J=7, 1H), 7.52 (m, 2H), 7.78 (m, 2H), 7.95 (dd, J=7, 8, 1H).

[0528]¹³C-NMR (CDCl₃, δ): 28.5, 31.1, 46.7, 46.8, 51.9, 112.0, 112.9,128.9, 131.1, 132.3, 141.3, 145.8, 148.1, 156.8.

[0529] MS (%): 297 (parent+1, 100), 197 (50), 133 (52).

[0530] Anal. Calc'd. for C₁₈H₂₄N₄3(C₂HF₃O₂) H₂O: C 43.91, H 4.45, N8.53. Found: C 43.82, H 4.11, N 8.48.

EXAMPLE 684-Amino-1-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperidine-4-carboxylicacid morpholine-amide

[0531] Prepared as in Example 1, using 4-amino-piperidine-4-carboxylicacid morpholine-amide, in 13% yield, mp>280° C. as the hydrochloridesalt.

[0532]¹H-NMR (CDCl₃, δ): 2.2-2.4 (m, 4H), 2.57 (m, 2H), 2.79 (m, 2H),2.8-2.9 (m, 4H), 3.5-3.7 (m, 8H), 4.48 (bs, 2H), 6.41 (d, J=8, 1H), 7.04(d, J=7, 1H), 7.24 (m, 2H), 7.46 (t, J=8, 1H), 7.81 (m, 2H).

[0533]¹³C-NMR (CDCl₃, δ): 33.4, 34.0, 37.0, 56.4, 49.9, 60.3, 61.3,67.1, 106.9, 110.7, 126.8, 128.9, 137.0, 138.3, 156.0, 158.2 (carbonylcarbon not visible in this scan).

[0534] MS (%): 410 (parent+1, 12), 242 (100)

[0535] not-Anal. Calc'd. for C₂₅H₂₉N₅O2HCl½H₂O¾CH₂Cl₂: C 55.1 1, H 6.02,N 12.48. Found: C 55.34, H 6.05, N 12.14.

EXAMPLE 694-Amino-1-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperidine-4-carboxylicacid pyrrolidine-amide

[0536] Prepared as in Example 1, using 4-amino-piperidine-4-carboxylicacid pyrrolidine-amide, in 39% yield, mp 220° C. (dec.) as thehydrochloride salt.

[0537]¹H-NMR (CDCl₃, δ): 1.8 (bs, 6H), 2.51 (m, 4H), 2.59 (m, 2H), 2.79(m, 2H), 3.4-3.6 (m, 4H), 3.8 (bs, 4H), 4.51 (bs, 2H), 6.39 (d, J=8,1H), 7.02 (d, J=7, 1H), 7.22 (m, 2H), 7.46 (t, J=8, 1H), 7.80 (m, 2H).

[0538]¹³C-NMR (CDCl₃, δ): 33.4, 35.6, 45.4, 48.0, 59.8, 56.1, 60.4,106.9, 110.7, 126.8, 128.9, 137.6, 138.3, 141.0, 156.0, 158.2, 173.8.

[0539] FAB MS (%): 394 (parent+1, 28), 197 (38), 149 (63), 133 (100).

[0540] Anal. Calc'd. for C₂₃H₃₁N₅OHCl¼H₂OCH₂Cl₂: C 55.50, H 6.64, N13.48. Found: C 55.79, H 6.85, N 13.10.

EXAMPLE 706-{4-[2-(3-Amino-pyrrolidin-1-yl)-ethyll-phenyl]-pyridin-2-ylamine

[0541] Prepared as in Example 1, using3-(t-butoxycarbonylamino)-pyrrolidine followed by deprotection usingtrifluoroacetic acid in methylene chloride at room temperature, in 92%yield, mp 135° C. (dec.) as the hydrochloride salt.

[0542]¹H-NMR (CDCl₃, δ): 1.4-1.5 (m, 3H), 2.16 (m, 1H), 2.37 (m, 1H),2.52 (m, 1H), 2.7-2.9 (m, 6H), 3.51 (m, 1H), 4.53 (bs, 2H, NH), 6.42 (d,J=8, 1H), 7.05 (d, J=7, 1H), 7.27 (m, 2H), 7.47 (t, J =8, 1H), 7.84 (m,2H).

[0543]¹³C-NMR (CDCl₃, δ): 35.2, 35.3, 51.0, 53.3, 58.0, 64.1, 106.8,110.7, 126.8, 128.8, 137.6, 138.3, 141.0, 156.1, 158,2.

[0544] MS (%): 283 (parent+1, 100), 197 (37), 99 (75).

[0545] Anal. Calc'd. for C₂₇H₂₂N₄3HClH₂O: C 49.83, H 6.64, N 13.67.Found: C 49.94, H 6.89, N 13.29.

EXAMPLE 71 1-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethylamino}-8-aza-bicyclo[3.2.1]oct-8-yl)-2-(4-fluoro-phenyl)-ethanone

[0546] Prepared as in Example 1, using1-amino-8-aza-bicyclo[3.2.1]oct-8-yl)-2-(4-fluoro-phenyl)-ethanone, in23.5% yield, mp 170° C. (dec.) as the hydrochloride salt.

[0547]¹H-NMR (CDCl₃, δ): 1.12 (m, 1H), 1.39 (m, 1H), 1.61 (m, 2H), 1.84(m, 4H), 2.79 (m, 4H), 2.97 (m, 1 H), 3.56 (dd, J=15, 35, 2H), 4.165 (m,1H), 4.49 (bs, 2H, NH), 4.68 (m, 1H), 6.42 (d, J=8, 1H), 6.96 (m, 2H),7.04 (d, J=8, 1H), 7.1-7.3 (m, 4H), 7.47 (t, J=8, 1H), 7.83 (m, 2H).

[0548]¹³C-NMR (CDCl₃, δ): 27.2, 28.9, 36.3. 38.3. 39.9, 40.4, 47.9,48.9, 51.1, 54.4, 107.0, 110.8, 115.3, 115.5, 127.0, 128.9, 130.3,131.0, 137.9, 138.4, 140.2, 155.9, 158.2, 162.9, 166.2.

[0549] MS (%): 459 (parent+1, 27), 133 (98), 110 (100), 109 (30).

[0550] Anal. Calc'd. for C₂₈H₃₁N₄OF2HCl¾H₂O: C 61.70, H 6.38, N 10.28.Found: C 61.82, H 6.43, N 10.11.

EXAMPLE 721-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-3-phenyl-urea

[0551] Prepared from Example 73, using phenylisocyanate, in 53.5% yield,mp 130° C. (dec.) as the hydrochloride salt from methylenechloride/ether.

[0552]¹H-NMR (CDCl₃, δ): 1.64 (m, 1H), 2.22 (m, 2H), 2.46 (m, 1H), 2.69(m, 2H), 2.79 (m, 4H), 2.97 (m, 1H), 4.25 (bs, 1H, NH), 4.54 (bs, 2H,NH), 5.94 (bs, 1H, NH), 6.40 (d, J=8, 1H), 6.9-7.0 (m, 3H), 7.2-7.3 (m,5H), 7.46 (t, J=8, 1H), 7.80 (m, 2H).

[0553]¹³C-NMR (CDCl₃, δ): 32.3, 34.7, 49.4, 53.1, 57.3, 61.0, 107.1,110.8, 119.9, 122.8, 126.9, 128.8, 129.0, 137.6, 138.5, 139.3, 140.6,155.8, 156.0, 158.4.

[0554] MS (%): 402 (parent+1, 97), 197 (48), 155 (48), 133 (100), 119(78), 103 (48).

[0555] Anal. Calc'd. for C₂₄H₂₇N₅O 2HCl½C₄H₁₀O½CH₂Cl₂: C 57.46, H 6.37,N 12.64. Found: C 57.74, H 6.35, N 12.44.

EXAMPLE 731-(1-{2-[4-(6-Amino-pyridin-2yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-3-benzyl-urea

[0556] Prepared from Example 73, using benzylisocyanate, in 42% yield,mp 90° C. (dec.) as the hydrochloride salt from methylenechloride/ether.

[0557]¹H-NMR (CDCl₃, δ): 1.65 (m, 1H), 2.19 (m, 2H), 2.45 (m, 1H),2.6-2.8 (m, 6H), 2.95 (m, 1H), 4.17 (m, 1H), 4.28 (d, J=6, 2H), 4.52 (m,2H, NH), 5.27 (m, 1H), 6.40 (d, J=8, 1H), 7.01 (d, J=7, 1H), 7.2-7.3 (m,7H), 7.45 (t, J=8, 1Hz, 7.79 (m, 2H).

[0558]³C-NMR (CDCl₃, δ): 32.4, 34.7, 44.3, 49.7, 53.0, 57.2, 61.0,107.0, 110.7, 126.8, 127.1, 127.5, 128.5, 128.8, 137.6, 138.4, 139.5,140.5, 155.9, 157.8, 158.2.

[0559] MS (%): 416 (parent+1, 100), 197 (52), 133 (63), 119 (55), 91(65).

[0560] Anal. Calc'd. for C₂₁H₂₉N₅O2HCl½C₄H₁₀O½CH₂Cl₂½H₂O: C 57.25, H6.64, N 12.14. Found: C 56.93, H 6.64, N 11.74.

EXAMPLE 741-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-3-cyclohexyl-urea

[0561] Prepared from Example 73, using cyclohexylisocyanate, in 27%yield, mp 120° C. (dec.) as the hydrochloride salt from methylenechloride/ether.

[0562]¹H-NMR (CDCl₃, δ): 1.02 (m, 3H), 1.26 (m, 3H), 1.50 (m, 1H), 1.60(m, 3H), 1.83 (m, 2H), 2.56 (m, 1H), 2.69 (m, 2H), 2.79 (m, 2H), 2.91(m, 1H), 3.47 (m, 1H), 4.18 (m, 1H), 5.50 (m, 1H), 6.38 (d, J=8, 1H),6.99 (d, J=7, 1H), 7.19 (m, 2H), 7.42 (d, J=8, 1H), 7.79 (m, 2H).

[0563]¹³C-NMR (CDCl₃, δ): 25.0, 25.6, 32.3, 33.9, 34.7, 48.7, 49.4,53.1, 57.5, 61.1, 107.0, .110.6, 126.9, 128.8, 137.7, 138.3, 140.4,155.8, 157.4, 158.4.

[0564] MS (%): 408 (parent+1, 95), 309 (62), 197 (100), 133 (61).

[0565] Anal. Calc'd. for C₂₄H₃₃N₅O2HCl½C₄H₁₀O½CH₂Cl₂{fraction (5/4)}H₂O:C 54.64, H 7.53, N 12.02. Found: C 54.52, H 7.28, N 12.00.

EXAMPLE 75{2-[4-6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-amine

[0566] Prepared as in Example 1, using(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-2-amine, in 27% yield, mp 98° C.(dec.) as the hydrochloride salt from ether.

[0567]¹H-NMR (CDCl₃, δ): 0.9-1.9 (multiplets, 8H), 2.49 (s, 3H), 2.8-3.0(m, 6H), 3.25 (m, 1H), 3.49 (bs, 2H, NH), 6.42 (d, J=8, 1H), 7.02 (d,J=7, 1H), 7.23 (m, 2H), 7.46 (t, J=8, 1H), 7.81 (m, 2H).

[0568] MS (%): 337 (parent+1, 100).

[0569] Anal. Calc'd. for C₂₁H₂₈N₄3HCl{fraction (5/2)}H₂O¼C₄H₁₀O: C51.87, H 7.62, N 11.00. Found: C 51.87, H 7.58, N 10.98.

EXAMPLE 76{2-[4-(6-Amino-1pyridin-2-yl)-phenyl]-ethyl}-(3-benzyl-3-aza-bicyclo[3.1.0]hex-6-yl)-amine

[0570] Prepared as in Example 1, using3-benzyl-3-aza-bicyclo[3.1.0]hex-6-amine, in 19% yield, as a tan solid,as the hydrochloride salt.

[0571]¹H-NMR (CDCl₃, δ): 1.42 (m, 2H), 2.38 (m, 2H), 2.51 (m, 1H), 2.84(m, 2H), 2.94 (m, 4H), 3.55 (s, 2H), 4.52 (bs, 2H, NH), 6.41 (d, J=8,1H), 7.04 (d, J=8, 1H), 7.2-7.3 (m, 7H), 7.46 (t, J=8, 1H), 7.83 (m,2H).

[0572]¹³C-NMR (CDCl₃, δ): 24.3, 35.7, 38.7, 50.5, 54.4, 59.1, 106.9,110.7, 126.8, 126.9, 128.2, 128.6, 128.9, 137.7, 138.4, 139.5, 140.4,156.0, 158.2.

[0573] MS (%): 385 (parent+1, 20), 155 (64), 119 (100).

[0574] not-Anal. Calc'd. for C₂₃H₃₁N₅OHCl¼H₂OCH₂Cl₂: C 55.50, H 6.64, N13.48. Found: C 55.79, H 6.85, N 13.10.

EXAMPLE 77{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-[8-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-amine

[0575] Prepared as in Example 1, using8-(4-fluoro-benzyl)-8-aza-bicyclo[3.2.1]oct-3-amine, in 22% yield, mp190° C. (dec.) as the hydrochloride salt.

[0576]¹H-NMR (CDCl₃, δ): 1.43 (m, 2H), 1.52 (m, 2H), 1.70 (m, 2H), 1.95(m, 2H), 2.7-2.8 (m, 5H), 3.14 (m, 2H), 3.50 (s, 2H), 4.49 (bs, 2H, NH),6.41 (d, J=8, 1H), 6.94 (m, 2H), 7.04 (d, J=8, 1H), 77.24 (m, 2H), 7.30(m, 2H), 7.46 (t, J=8, 1H), 7.83 (m, 2H).

[0577]¹³C-NMR (CDCl₃, δ): 27.0, 36.4, 38.3, 48.0, 48.9, 54.8, 58.3,106.9, 110.7, 114.7, 114.9, 126.7, 126.8, 126.9, 128.9, 129.8, 129.9,135.9, 137.8, 138.3, 140.6, 156.0, 158.2, 160.5, 162.9.

[0578] MS (%): 431 (parent+1, 44), 218 (56), 109 (100).

[0579] Anal. Calc'd. for C₂₇H₃₁N₄F3HCl{fraction (3/2)}H₂O: C 57.20, H6.58, N 9.88. Found: C 57.30, H 6.91, N 9.56.

EXAMPLE 78{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-[8-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-amine

[0580] Prepared as in Example 1, using8-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]oct-3-amine, in 29% yield, mp198° C. (dec.) as the hydrochloride salt.

[0581]¹H-NMR (CDCl₃, δ): 1.42 (m, 2H), 1.52 (m, 2H), 1.68 (m, 2H), 1.94(m, 2H), 2.8-2.9 (m, 5H), 3.13 (bs, 2H), 3.49 (s, 2H), 4.53 (bs, 2H,NH), 6.40 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.2-7.3 (m, 7H), 7.45 (t,J=8, 1H), 7.82 (m, 2H).

[0582]¹³C-NMR (CDCl₃, δ): 24.0, 36.2, 37.9, 47.9, 49.0, 54.8, 58.1,107.0, 110.7, 126.8, 127.0, 128.2, 128.3, 128.9, 129.8, 130.0, 132.2,137.8, 138.4, 138.7, 140.4, 156.0, 158.2.

[0583] MS (%): 447 (parent+1, 45), 234 (54), 125 (100).

[0584] Anal. Calc'd. for C₂₇H₃₁N₄Cl3HCl½H₂O: C 57.36, H 6.24, N 9.91.Found: C 57.27, H 6.44, N 9.57.

EXAMPLE 794-Amino-1-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperidine-4-carboxylicacid phenethyl-amide

[0585] Prepared as in Example 1, using 4-amino-piperidine-4-carboxylicacid phenethyl-amide, in 12% yield, mp 215-219° C. (dec.) as thehydrochloride salt.

[0586]¹H-NMR (CDCl₃, δ): 1.31 (m, 2H), 1.80 (bs, 2H), 2.25 (m, 4H), 2.62(m, 2H), 2.8-3.0 (m, 6H), 3.48 (m, 2H), 4.49 (bs, 2H, NH), 6.41 (d, J=8,1H), 7.04 (d, J7, 1H), 7.2-7.4 (m, 7H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0587]¹³C-NMR (CDCl₃, δ): 33.4, 35.0, 35.8, 40.4, 49.0, 55.2, 60.4,106.9, 110.7, 126.4, 126.8, 128.5, 128.8, 128.9, 137.6, 138.3, 139.1,140.9, 156.0, 158.2, 176.9.

[0588] MS (%): 444 (parent+1, 15), 197 (54), 133 (100).

[0589] Anal. Calc'd. for C₂₇H₃₃N₅O3HCl: C 58.65, H 6.56, N 12.66. Found:C 58.29, H 6.97, N 12.28.

EXAMPLE 803-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethylamino}-pyrrolidine-1-carboxylicacid phenylamide

[0590] Prepared as in Example 1, using 3-amino-pyrrolidine-1-carboxylicacid phenylamide, in 8% yield, mp 130° C. (dec.) as the hydrochloridesalt from ethyl ether.

[0591]¹H-NMR (CDCl₃, δ): 1.64 (m, 1H), 2.20 (m, 2H), 2.46 (dd, J=3,7,1H), 2.66 (m, 2H), 2.78 (m, 4H), 2.97 (m, 1H), 4.25 (bs, 1H, NH), 4.53(bs, 2H, NH), 5.85 (d, J=7, 1H), 6.40 (d, J=8, 1H), 6.9-7.0 (m, 3H),7.2-7.3 (m, 5H), 7.46 (t, J=8, 1H), 7.79 (m, 2H).

[0592]¹³C-NMR (CDCl₃, δ): 32.4, 34.8, 49.6, 53.1, 57.3, 61.0, 107.1,110.8, 120.0, 122.9, 126.9, 128.8, 129.0, 137.6, 138.4, 139.2, 140.7,155.6, 156.0, 158.3.

[0593] MS (%): 402 (parent+1, 100), 283 (20), 264 (18).

[0594] Anal. Calc'd. for C₂₄H₂₇N₅O2HClH₂OC₄H₁₀O: C 59.36, H 7.29, N12.36. Found: C 59.34, H 6.69, N 12.59.

EXAMPLE 81(3-{2-[4-(6-Amino-pyridin,2-yl)-phenyl-ethylamino}-pyrrolidin-1-yl)-phenyl-methanone

[0595] Prepared as in Example 1, using3-amino-pyrrolidin-1-yl-phenyl-methanone, in 10% yield, mp 130° C.(dec.) as the hydrochloride salt from ethyl ether.

[0596]¹H-NMR (CDCl₃, δ): 1.71 (m, 1H), 1.98 and 2.13 (multiplets, 1H),2.7-3.0 (m, 3H), 3.2-3.8 (multiplets, 6H), 4.51 (bs, 2H, NH), 6.42 (d,J=8, 1H), 7.04 (t, J=7, 1H), 7.20 (d, J=8, 1H), 7.26 (m, 1H), 7.38 (m,3H), 7.46 (m, 3H), 7.83 (m, 2H).

[0597]¹³C-NMR (CDCl₃, δ): 30.8, 32.5, 36.0, 44.7, 47.8, 49.2, 49.3,52.1, 55.1, 56.3, 57.9, 107.0, 110.75, 127.0, 127.1, 128.2, 128.3,128.9, 129.9, 137.9, 138.4, 140.0, 155.8, 158.2, 169.8.

[0598] MS (%): 387 (parent+1, 75), 155 (44), 119 (100), 105 (60).

[0599] Anal. Calc'd. for C₂₄H₂₈N₄OHCl½CH₂Cl₂C₄H₁₀O: C 63.44, H 7.10, N10.38. Found: C 63.33, H 6.72, N 10.39.

EXAMPLE 826-{4-[2-(1-Benzyl-pyrrolidin-3-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0600] Prepared as in Example 1, using 1-benzyl-pyrrolidin-3-ylamine, in27% yield, mp 145° C. (dec.) as the hydrochloride salt.

[0601]¹H-NMR (CDCl₃, δ): 1.49 (m, 1H), 2.08 (m, 1H), 2.26 (dd, J=5, 9,1H), 2.73 (m, 1H), 2.81 (s, 4H), 3.29 (m, 1H), 3.56 (A8q, J=19, Dn=13,2H), 4.52 (bs, 2H, NH), 6.39 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.28 (m,7H), 7.45 (t, J=8, 1H), 7.83 (m, 2H).

[0602]³C-NMR (CDCl₃, δ): 32.1, 36.3, 49.5, 53.0, 57.3, .60.5, 60.7,106.9, 110.7, 126.88, 126.94, 128.2, 128.8, 128.9, 137.8,138.3, 139.0,140.5, 156.0, 158.3.

[0603] MS (%): 373 (parent+1, 100), 155 (35), 119 (78), 103 (35).

[0604] Anal. Calc'd. for C₂₄H₂₈N₄3HCl½H₂O: C 58.72, H 6.57, N 11.41.Found: C 58.37, H 6.67, N 11.23.

EXAMPLE 83N-(8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide

[0605] Prepared as in Example 1, using8-aza-bicyclo[3.2.1]oct-3-yl)-benzamide, in 29% yield, mp 211° C. (dec.)as the hydrochloride salt.

[0606]¹H-NMR (CDCl₃, δ): 1.67 (m, 2H), 1.78 (m, 2H), 1.92 (m, 2H), 2.00(m, 2H), 3.39 (m, 2H), 4.36 (m, 1H), 4.47 (bs, 2H, NH), 5.96 (d, J=8,1H), 6.42 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.26 (m, 2H), 7.40 (m, 2H),7.47 (m, 2H), 7.70 (m, 2H), 7.82 (m, 2H).

[0607]³C-NMR (CDCl₃, δ): 26.4, 35.4, 37.65, 41.6, 53.8, 59.2, 106.9,110.7, 126.8, 128.5 .,128.9, 131.4, 134.7, 137.7, 138.3, 140.7, 156.0,158.2, 166.7.

[0608] MS (%): 427 (parent+1, 100).

[0609] Anal. Calc'd. for C₂₇H₃₀N₄O2HClH₂O: C 62.67, H 6.62, N 10.83.Found: C 62.85, H 6.57, N 10.52.

EXAMPLE 84{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-benzyl-3-aza-bicyclo[3.3.1]non-9-yl)-amine

[0610] Prepared as in Example 1, using(3-benzyl-3-aza-bicyclo[3.3.1]non-9-yl)-amine, in 24% yield, mp 190° C.(dec.) as the hydrochloride salt, as a mixture of endo and exo isomers.

[0611]¹H-NMR (CDCl₃, δ): 1.44 (m, 2H), 1.76 (m, 4H), 2.37 (m, 2H), 2.55(m, 2H), 2.86 (s, 4H), 2.94 (m, 2H), 3.28 and 3.27 (singlets, 2H, endoand exo isomers in roughly 1:1 ratio, N-benzyl CH₂ group), 4.47 (bs, 2H,NH), 6.44 (dd, J=2, 8, 1H), 7.07 (dd, J=3, 7, 1H), 7.1-7.3 (m, 7H), 7.47(dt, J=2, 8, 1H), 7.86 (m, 2H).

[0612]¹³C-NMR (CDCl₃, δ): 21.2, 24.5, 32.3, 33.0, 47.8, 53.1, 60.2,63.5, 63.8, 106.9, 110.7, 126.2, 126.6, 126.9, 128.1, 128.2, 128.6,128.7, 128.9, 129.0, 138.3, 139.0, 141.0, 158.0, 159.0.

[0613] MS (%): 427 (parent+1, 68), 91 (100).

[0614] Anal. Calc'd. for C₂₈H₃₄N₄3HCl½H₂O. C 61.71, H 7.03, N 10.28.Found: C 61.86, H 7.19, N 9.97.

EXAMPLE 85N-(8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2-(4-fluoro-phenyl)-acetamide

[0615] Prepared as in Example 1, using8-aza-bicyclo[3.2.1]oct-3-yl)-2-(4-fluoro-phenyl)-acetamide, in 23%yield, mp 160° C. (dec.) as the hydrochloride salt.

[0616]¹H-NMR (CDCl₃, δ): 1.49 (m, 2H), 1.69 (m, 2H), 1.76 (m, 2H), 1.93(m, 2H), 2.58 (m, 2H), 2.81 (m, 2H), 3.33 (bs, 2H), 3.44 (s, 2H), 3.49(s,1 H), 4.13 (m,1H), 4.49 (bs, 2H, NH), 6.41 (d, J=8, 1H), 7.01 (m,3H), 7.21 (m, 4H), 7.45 (t, J=8, 1H), 7.81 (m, 2H).

[0617]¹³C-NMR (CDCl₃, δ): 26.1, 35.1, 37.6, 37.8, 41.0, 42.9, 52.9,54.0, 59.4, 107.0, 110.7, 115.7, 115.9, 126.9, 127.3, 128.9, 129.0,129.4, 130.9, 137.8, 138.4, 140.3, 155.9, 158.2, 170.1.

[0618] MS (%): 459 (parent+1, 100), 197 (21), 119 (31), 103 (36).

[0619] Anal. Calc'd. for C₂₈H₃₁N₄FO2HCl½H₂O: C 62.22, H 6.34, N 10.37.Found: C 61.99, H 6.50, N 10.01.

EXAMPLE 866-{4-[2-(3-Amino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0620] Prepared as in Example 1, using3-(t-butoxycarbonylamino)-piperidine, in 100% yield followingcondensation with (6-amino-pyridin-2-yl)-phenyl]-2-chloroethane anddeblocking with trifluoroacetic acid in methylene chloride, mp 150° C.(dec.) as the hydrochloride salt.

[0621]¹H-NMR (CDCl₃, δ): 1.20 (m, 1H), 1.42 (m, 1H), 1.62 (m, 1H), 1.85(m, 1H), 2.31 (td, J=2, 9, 1H), 2.51 (m, 2H), 2.79 (m, 2H), 2.86 (m,3H), 3.08 (m, 1H), 4.52 (bs, 2H, NH), 6.39 (dd, J=1, 8, 1H), 7.02 (, dd,J=1, 7, 1H), 7.23 (m, 2H), 7.44 (td, J=1, 8, 1H), 7.81 (m, 2H).

[0622]¹³C-NMR (CDCl₃, δ): 25.1, 31.8, 36.3, 46.6, 48.1, 52.4, 54.75,106.9, 110.7, 126.9, 128.9, 137.7, 138.3, 140.5, 156.0, 158.2.

[0623] MS (%): 297 (parent+1, 57), 135 (40), 119 (100), 103 (62).

[0624] Anal. Calc'd. for C₁₈H₂₄N₄3HClH₂O½CH₂Cl₂: C 51.70, H 6.80, N13.03. Found: C 51.90, H 6.64, N 12.59.

EXAMPLE 87N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.1]non-9-yl)-benzamide,anti-isomer

[0625] Prepared as in Example 1, using3-aza-bicyclo[3.3.1]non-9-yl)-benzamide, anti-isomer, in 18% yield, mp185° C. (dec.) as the hydrochloride salt.

[0626]¹H-NMR (CDCl₃, δ): 1.35 (m, 1H), 1.71 (m, 4H), 1.95 (m, 2H),2.4-2.5 (m, 5H), 2.79 (m, 2H), 3.04 (m, 2H), 4.10 (m, 1H), 4.53 (bs, 2H,NH), 6.41 (dd, J-1, 8, 1H), 6.42 (m, 1H), 7.05 (dd, J=1, 7, 1H), 7.25(m, 2H), 7.4-7.5 (m, 4H), 7.75 (m, 2H), 7.84 (m, 2H).

[0627]¹³C-NMR (CDCl₃, δ): 20.6, 25.3, 32.9, 33.5, 51.4, 59.5, 59.9,106.8, 110.6, 126.6, 126.8, 128.6, 158.9, 131.3, 135.1, 137.3, 138.3,141.5, 156.1, 158.2, 166.9.

[0628] MS (%): 441 (parent+1, 41), 149 (75), 119 (100).

[0629] Anal. Calc'd. for C₂₈H₃₂N₄O2HCl½H₂O¼(C₄H₁₀): C 64.38, H 6.99, N10.36. Found: C 64.49, H 6.43, N 9.91.

EXAMPLE 88N-(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.1]non-9-yl)-benzamide,syn-isomer

[0630] Prepared as in Example 1, using3-aza-bicyclo[3.3.1]non-9-yl)-benzamide, syn-isomer, in 9% yield, as ahygroscopic solid as the hydrochloride salt.

[0631]¹H-NMR (CDCl₃, δ): 1.37 (m, 1H), 1.81 (m, 4H), 2.00 (m, 2H), 2.33(m, 1H), 2.51 (m, 4H), 2.83 (m, 4H), 4.04 (m, 1H), 4.48 (bs, 2H, NH),6.42 (dd, J=1, 8, 1H), 7.05 (dd, J=1, 7, 1H), 7.24 (m, 2H), 7.4-7.5 (m,4H), 7.74 (m, 2H), 7.82 (m, 2H).

[0632]¹³C-NMR (CDCl₃, δ): 20.3, 31.9, 33.4, 33.7, 50.8, 53.8, 60.5,107.1, 110.7, 126.7, 126.8, 128.6, 128.9, 131.3, 135.1, 137.0, 138.6,141.4, 155.6, 158.1, 166.6.

[0633] MS (%): 441 (parent+1, 5), 391 (10), 167 (23), 149 (100).

[0634] Anal. Calc'd. for C₂₈H₃₂N₄OHCl½CH₂Cl₂½(C₄H₁₀O): C 65.82, H 7.06,N 10.07. Found: C 66.20, H 6.80, N 10.10.

EXAMPLE 896-{4-[2-(4-Benzhydryl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0635] Prepared as in Example 1, using 4-benzhydryl-piperazine, in 54%yield, mp 170° C. dec.) as the hydrochloride salt.

[0636]¹H-NMR (CDCl₃, δ): 2.45 (m, 4H), 2.56 (m, 4H), 2.61 (m, 2H), 2.82(m, 2H), 4.24 (s, 1H), 4.54 (bs, 2H, NH), 6.37 (d, J=8, 1H), 7.04 (d,J=8, 1H), 7.19 (m, 2H), 7.26 (m, 6H), 7.42 (m, 5H), 7.85 (m, 2H).

[0637]¹³C-NMR (CDCl₃, δ): 33.4, 51.9, 52.0, 53.5, 60.4, 106.8, 110.6,126.8, 126.9, 128.0, 128.5, 128.9, 137.6, 138.3, 141.0, 142.8, 156.0,158.3.

[0638] MS (%): 449 (parent+1, 17), 253 (12), 167 (100), 149 (14).

[0639] Anal. Calc'd. for C₃₀H₃₂N₄2HCl¼CH₂Cl₂: C 66.94, H 6.41, N 10.32.Found: C 66.57, H 6.22, N 10.17.

EXAMPLE 906-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0640] Prepared as in Example 1, using 4-benzhydryl-piperidine, in 24%yield, mp 175° C. (dec.) as the hydrochloride salt.

[0641]¹H-NMR (CDCl₃, δ): 1.32 (m, 2H), 1.56 (m, 2H), 2.11 (m, 2H), 2.14(m, 1H), 2.61 (m, 2H), 2.83 (m, 2H), 2.99 (m, 2H), 3.50 (d, J=11, 1H),4.46 (bs, 2H, NH), 6.41, (dd, J=0.5, 8, 1H), 7.04 (dd, J=0.5, 7.5, 1H),7.14 (m, 2H), 7.2-7.3 (m, 10H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0642]¹³C-NMR (CDCl₃, δ): 31.2, 33.4, 39.5, 53.9, 58.9, 60.6, 106.9,110.7, 126.2, 126.8, 128.0, 128.5, 128.9, 138.3, 143.7, 156.0, 158.2.

[0643] MS (%): 448 (parent+1, 100), 264 (32), 149 (70).

[0644] Anal. Calc'd. for C₃₁H₃₃N₃ 2HCl¼CH₂Cl₂: C 69.28, H 6.60, N 7.76.Found: C 68.96, H 6.48, N 7.36.

EXAMPLE 913-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.3.1]non-9-ylamine

[0645] Prepared as in Example 1, using 3-aza-bicyclo[3.3.1]non-9-ylaminet-butylcarbamate followed by deprotection using trifluoroacetic acid inmethylene chloride in 85% yield, as a low-melting solid as thehydrochloride salt.

[0646]¹H-NMR (CDCl₃, δ): 1.28 (m, 1H), 1.48 (m, 2H), 1.61 (bs, 2H), 1.82(m, 2H), 2.26 (m, 2H), 2.35 (m, 1H), 2.46 (t, J=7, 2H), 2.78 (m, 3H),3.02 (m, 2H, 4.46 (bs, 2H, NH), 6.41 (dd, J=0.5,8, 1H), 7.05 (d, J=0.6,7, 1H), 7.24 (m, 2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0647]¹³C-NMR (CDCl₃, δ): 20.9, 24.1, 33.7, 36.1, 52.8, 60.2, 106.7,110.7, 126.6, 128.9, 137.2, 138.3, 141.7, 156.2, 158.1.

[0648] MS (%): 337 (parent+1, 13), 279 (14), 167 (30), 149 (100), 113(39).

[0649] Anal. Calc'd. for C₂₁H₂₉N₄2HCl½CH₂Cl₂(C₄H₁₀O): C 58.23, H 7.86, N10.65. Found: C 58.15, H 7.31, N 10.72.

EXAMPLE 923-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid ethyl ester

[0650] Prepared as in Example 1, using3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester in 18% yield,as a low melting solid as the hydrochloride salt.

[0651]¹H-NMR (CDCl₃, δ): 1.23 (t, J=7, 3H), 1.93 (bs, 2H), 1.99 (bs,1H), 2.40 (d, J=9, 1H), 2.65 (m, 2H), 2.71 (m, 2H), 3.12 (d, J=9, 2H),4.49 (bs, 2H, NH), 6.40 (d, J=8, 1H), 7.04 (d, J=7.5, 1H), 7.21 (m, 2H),7.45 (t, J=7.5, 1H), 7.81 (m, 2H).

[0652]¹³C-NMR (CDCl₃, δ): 14.3, 21.8, 26.3, 35.1, 54.4, 56.4, 30.2,106.8, 110.7, 126.7, 128.8, 137.5, 138.3, 141.0, 156.1, 158.2, 173.9.

[0653] MS (%): 352 (parent+1, 5), 167 (22), 149 (100), 113 (20).

[0654] Anal. Calc'd. for C₂₁H₂₅N₃O₂2HCl: C, H , N . Found: C , H. N

EXAMPLE 933-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hexane-6-carboxylicacid

[0655] Prepared by hydrolysis of Example 92 using 2N hydrochloric acidat 70° C. for 8 h in 83% yield, as a low-melting solid as thehydrochloride salt.

[0656]¹H-NMR (HCl salt, CDCl₃, δ): 2.18 (s, 2H), 2.31 (m, 2H), 3.28 (s,1H), 3.4-3.6 (m, 4H), 3.89 (m, 2H), 6.96 (m, 1H), 7.15 (m, 1H), 7.53 (m,2H), 7.79 (m, 2H), 7.94 (m, 1H).

[0657]¹³C-NMR (CDCl₃, δ): 24.3, 29.2, 31.5, 38.8, 55.7, 110.7, 111.6,124.7, 127.6, 128.5, 130.0, 130.6, 131.0, 140.0, 144.6, 146.4, 155.4,167.9.

[0658] MS (%): 324 (parent+1, 3), 279 (11), 167 (25), 149 (100), 129(12), 113 (27).

[0659] HRMS Calc'd. for C₁₉H₂₂N₃O₂ (parent+1): 324.1712. Found:324.1717.

EXAMPLE 943-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethylamino}-piperidine-1-carboxylicacid tert-butyl ester

[0660] Prepared as in Example 1, using piperidine-1-carboxylic acidtert-butyl ester in 29% yield as a foam.

[0661]¹H-NMR (CDCl₃, δ): 1.43 (s, 9H), 1.0, 1.8 (m, 3H), 2.35 (m, 2H),2.54 (m, 3H), 2.76 (t, J=8, 2H), 3.74 (m, 1H), 4.55 (bs, 2H), 5.03 (bs,1H), 6.39 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.22 (m, 2H), 7.44 (t, J=8,1H), 7.83 (m, 2H).

[0662]¹³C-NMR (CDCl₃, δ): 22.3, 28.5, 29.7, 33.3, 46.3, 53.8, 58.5,60.3, 78.9, 106.8, 110.6, 126.8, 128.9, 13.5, 138.3, 141.0, 155.2,156.0, 158.3.

[0663] MS (%): 397 (parent+1, 56), 297 (38), 280 (48), 213 (40), 197(95), 157 (100).

[0664] HRMS Calc'd. for C₂₃H₃₃N₄O₂ (parent+1): 397.26035. Found: C397.2581.

EXAMPLE 956-{4-[2-(Piperidin-3-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0665] Prepared by deprotection of Example 94 using trifluoroacetic acidin methylene chloride in 92% yield, as the hydrochloride salt from ethylether.

[0666]¹H-NMR (CDCl₃, δ): 1.35 (bs, 2H), 1.58 (m, 1H), 1.69 (m, 1H), 1.85(m, 1H), 2.07 (m, 1H), 2.60 (m, 2H), 2.74 (m, 1H), 2.79 (m, 2H), 2.81(m, 4H), 4.47 (bs, 2H), 6.41 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.23 (m,2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0667]¹³C-NMR (CDCl₃, δ): 23.8, 33.3, 34.2, 48.1, 53.6, 60.6, 62.7,106.8, 110.7, 126.8, 128.9, 137.5, 138.3, 141.1, 156.0, 158.2.

[0668] FAB MS (%): 297 (parent+1,12),167 925),149 (100),119 (27),111(25).

[0669] Anal. Calc'd. for C₁₈H₂₄N₄ 3HClH₂O¼(C₄H₁₀O): C 51.59, H 7.18, N12.67. Found: C 51.86, H 7.23, N 12.31.

EXAMPLE 96 6-{4-[2-(1-Benzyl-piperidin-4-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0670] Prepared as in Example 1, using 1-benzyl-4-aminopiperidine in 82%yield (purification was effected by forming the t-butylcarbamatederivative followed by chromatography and deprotection withtrifluoroacetic acid in methylene chloride), as the hydrochloride salt.

[0671]¹H-NMR (CDCl₃, δ): 1.38 (m, 2H), 1.80 (m, 2H), 1.99 (m, 2H), 2.46(m, 1H), 2.83 (m, 4H), 2.90 (m, 2H), 3.48 (s, 2H), 4.57 (bs, 2H), 6.40(d, J=8, 1H), 7.05 (d, J =7, 1H), 7.30 (m, 7H), 7.45 (t, J =8, 1H), 7.85(m, 2H).

[0672]¹³C-NMR (CDCl₃, δ): 32.7, 36.3, 48.0, 52.5, 54.9, 36.1, 106.9,110.7, 126.9, 128.2, 128.9, 129.1, 137.8, 138.3, 138.6, 140.6, 156.0,158.3.

[0673] FAB MS (%): 387 (parent+1,47), 174(31), 149 (100), 119 (97), 103(52).

[0674] HRMS Calc'd. for C₂₅H₃₀N₄: 387.254°. Found: 387.2582.

EXAMPLE 973-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine(anti-isomer)

[0675] Prepared as in Example 1, using 3-aza-bicyclo[3.1.0]hex-6-ylamine(anti-isomer) t-butylcarbamate followed by deprotection usingtrifluoroacetic acid in methylene chloride in 79% yield, as thehydrochloride salt from ethyl ether.

[0676]¹H-NMR (CDCl₃, δ): 1.34 (m, 2H), 1.90 (bs, 2H), 2.29 (t, J=7, 1H),2.63 (m, 2H), 2.69 (m, 2H), 2.76 (m, 2H), 3.09 (d, J=9, 2H), 4.52 (bs,2H, 6.41 (d, J=8, 1H), 7.04 (d, J=8, 1H), 7.22 (m, 2H), 7.45 (t, J=8,1H), 7.82 (m, 2H).

[0677]¹³C-NMR (CDCl₃, δ): 19.9, 34.4, 35.4, 52.7, 57.0, 106.8, 110.7,126.7, 128.8, 137.5, 138.3, 141.2, 156.1, 158.2.

[0678] FAB MS (%): 295 (parent+1, 3), 279 (10), 167 (20), 149 (100), 129(6), 11 3 (25).

[0679] Anal. Calc'd. for C₁₈H₂₂N₄2HCl¼CH₂Cl₂½(C₄H₁₀{fraction (5/4)}H₂O:C 54.27, H 7.20, N 12.50. Found: C 53.92, H 6.83, N 12.19.

EXAMPLE 986-{4-[2-(Piperidin-4-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0680] Prepared by deblocking Example 96 using ammonium formate and 10%palladium-on-carbon in refluxing ethanol in 67.5% yield, as thehydrochloride salt from ethyl ether.

[0681]¹H-NMR (CDCl₃, δ): 1.30 (m, 2H), 1.87 (m, 2H), 2.65 (m, 3H), 2.81(m, 2H), 2.88 (m, 2H), 3.13 (m, 2H), 4.54 (bs, 2H), 6.42 9d, J=8, 1H),7.04 (d, J=8, 1H), 7.25 (m, 2H), 7.46 (t, J =8, 1H), 7.83 (m, 2H).

[0682]¹³C-NMR (CDCl₃, δ): 32.3, 36.1, 44.2, 47.7, 53.9, 107.0, 110.7,127.0, 128.9, 137.8, 138.4, 140.3, 155.95, 158.3.

[0683] MS (%): 297 (parent+1, 10), 199 (35), 149 (100), 119 (30).

[0684] Anal. Calc'd. for C₁₈H₂₄N₄3HCl¼H₂O½(C₄H₁₀O): C 53.70, H 7.32, N12.52. Found: C 53.61, H 6.99, N 12.18.

EXAMPLE 996-(4-{2-[(Piperidin-4-ylmethyl)-amino]-ethyl}-phenyl)-pyridin-2-ylamine

[0685] Prepared as in Example 1, using4-aminomethylpiperidine-1-t-butylcarbamate followed by deprotectionusing trifluoroacetic acid in methylene chloride in 80.5% yield, as thehydrochloride salt.

[0686]¹H-NMR (CDCl₃, δ): 1.25 (m, 3H), 1.87 (m, 2H), 2.65 (m, 2H), 2.81(m, 2H), 2.88 (m, 2H), 3.13 (m, 2H), 4.54 (bs, 2H), 6.42 (d, J=8, 1H),7.04 (d, J=8, 1H), 7.26 (m, 2H), 7.46 (t, J=8, 1H), 7.83 (m, 2H).

[0687]¹³C-NMR (CDCl₃, δ): 32.3, 36.1, 44.2, 47.7, 53.9, 107.0, 110.7,127.0, 128.9, 137.8, 138.4, 140.3, 155.95, 158.3.

[0688] FAB MS (%): 297 (parent+1, 16), 199 (35), 149 (100), 119 (30).

[0689] Anal. Calc'd. for C₁₉H₂₆N₄3HCl{fraction (7/4)}H₂O¾(C₄H₁₀O): C52.12, H 7.95, N 11.05. sound: C 52.62, H 7.59, N 10.96.

EXAMPLE 100(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-(4-methyl-piperazin-1-yl)-methanone

[0690] Prepared as in Example 1, using3-aza-bicyclo[3.1.0]hex-6-yl)-(4-methyl-piperazin-1-yl)-methanone in 14%yield, as the hydrochloride salt.

[0691]¹H-NMR (CDCl₃, δ): 1.94 (bs, 2H), 2.09 (bs, 1H), 2.2-2.4 (m, 8H),2.27 (s, 3H), 2.68 (m, 2H), 2.73 (m, 2H), 3.11 (m, 2H), 3.61 (m, 4H),4.49 (bs, 2H), 6.41 (d, J=8, 1H), 7.03 (d, J=8, 1H), 7.21 (m, 2H), 7.45(t, J=8, 1H), 7.81 (m, 2H).

[0692]¹³C-NMR (CDCl₃, δ): 19.7, 25.6, 35.1, 41.8, 45.5, 46.0, 54.5,54.7, 55.3, 56.7, 106.9, 110.7, 126.7, 1228.8, 137.5, 138.3, 140.9,156.0, 158.0, 171.1.

[0693] MS (%): 406 (parent+1, 3), 391 (20), 167 (18), 149 (100), 113(19).

[0694] Anal. Calc'd. for C₂₄H₃₁N₅O3HCl2H₂O{fraction (5/4)}(C₄H₁₀O): C54.12, H 7.91, N 10.88. Found: C 53.97, H 7.57, N 10.56.

EXAMPLE 101{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine(more polar diastereomer)

[0695] Prepared as in Example 1, using(9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine, more polardiastereomer, in 38% yield, as a foam as the hydrochloride salt.

[0696]¹H-NMR (CDCl₃, δ): 1.52 (m, 2H), 2.26 (m, 2H), 2.56 (m, 2H), 2.88(m, 4H), 2.97 (m, 1H), 3.47 (m, 2H), 3.79 (s, 2H), 3.82 (m, 2H), 4.50(bs, 2H), 6.41 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.2-7.4 (m, 7H), 7.46(t, J=8, 1H), 7.83 (m, 2H).

[0697]¹³C-NMR (CDCl₃, δ): 27.4, 36.7, 48.4, 49.0, 50.8, 56.1, 69.5,106.8, 110.7, 126.7, 127.0, 128.3, 128.5, 128.9, 137.5, 138.3, 139.0,141.2, 156.1, 158.2.

[0698] MS (%): 429 (parent+1, 42), 216 (53), 91 (100).

[0699] Anal. Calc'd. for C₂₇H₃₂N₄O 3HClH₂O: C 58.33, H 6.71, N 10.08.Found: C 58.12, H 6.82, N 9.83.

EXAMPLE 102{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine(less polar diastereomer)

[0700] Prepared as in Example 1, using(9-benzyl-3-oxa-9-aza-bicyclo[3.3.1 ]non-7-yl)-amine, less polardiastereomer, in 32% yield, mp 215° C. (dec.) as the hydrochloride salt.

[0701]¹H-NMR (CDCl₃, δ): 1.74 (m, 4H), 2.685 (bs, 2H), 2.86 (m, 2H),2.97 (m, 2.97 (m, 3H), 3.80 (s, 2H), 3.87 (m, 2H), 4.52 (bs, 2H), 6.42(d, J=8, 1H), 7.06 (d, J=7, 1H), 7.2-7.4 (m, 7H), 7.47 (t, J=8, 1H),7.86 (m, 2H).

[0702]¹³C-NMR (CDCl₃, δ): 31.3, 36.4, 47.8, 50.8, 52.5, 55.9, 71.4,106.9, 110.75, 127.0, 128.3, 128.5, 129.0, 137.8, 138.4, 139.2, 140.6,156.1, 158.3.

[0703] MS (%): 429 (parent+1, 12), 216 (67), 91 (100).

[0704] Anal. Calc'd. for C₂₇H₃₂N₄O3HClH₂O: C 58.33, H 6.71, N 10.08.Found: C 58.30, H 6.78, N 9.92.

EXAMPLE 1032-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanol

[0705] Prepared from Example 16, using sodium borohydride in methanol atroom temperature for 2 h in 98.5% yield, mp 235° C. (dec.) as thehydrochloride salt.

[0706]¹H-NMR (CDCl₃, δ): 2.51 (m, 6H), 2.63 (m, 4H), 2.82 (m, 4H), 4.10(bs,1H), 4.54 (bs, 2H), 4.74 (m, 1H), 6.39 (d, J=8, 1H), 7.05 (d, J=8,1H), 7.2-7.4 (m, 7H), 7.45 (t, J=8, 1H), 7.84 (m, 2H).

[0707]¹³C-NMR (CDCl₃, δ): 33.4, 53.3, 60.3, 66.2, 68.8, 106.9, 110.7,125.9, 126.9, 127.5, 128.4, 128.9, 137.7, 138.3, 140.8, 142.2, 156.0,158.3.

[0708] MS (%): 403 (parent+1, 100), 295 (54), 219 (41), 197 (76), 113(35), 97 (89).

[0709] Anal. Calc'd. for C₂₅H₃₀N₄O3HCl½H₂O: C 57.64, H 6.58, N 10.76.Found: C 57.66, H 6.45, N 10.77.

EXAMPLE 104{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine

[0710] Prepared from Example 101, using ammonium formate andpalladium-on-carbon in refluxing ethanol in 81% yield, mp 100° C. (dec.)as the hydrochloride salt.

[0711]¹H-NMR (CDCl₃, δ): 1.69 (m, 1H), 2.06 (m, 1H), 2.6-3.0 (m, 5H),3.5-3.9 (m, 4H), 4.64 (bs, 2H), 6.35 (d, J=8, 1H), 7.00 (d, J=8, 1H),7.23 (m, 2H), 7.40 (t, J=8, 1H), 7.81 (m, 2H).

[0712] MS (%): 339 (parent+1, 100), 254 (35), 199 (45), 159 (38).

[0713] HRMS Calc'd. for C₂₀H₂₇N₄O (parent+1): 339.2184. Found: 339.2164.

EXAMPLE 1056-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine

[0714] Prepared from Example 16, by forming the oxime methyl ether withO-methyl, hydroxylamine hydrochloride in refluxing methanol followed byreduction using borane methyl sulfide in refluxing tetrahydrofuran in54% yield, as the hydrochloride salt.

[0715]¹H-NMR (CDCl₃, δ): 2.2-2.9 (m, 14H), 4.12 (m, 1H), 4.52 (bs, 2H),6.39 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.2-7.4 (m, 7H), 7.45 (t, J=7,1H), 7.81 (m, 2H).

[0716] MS (%): 402 (parent+1, 6), 149 (100), 119 (47).

[0717] HRMS Calc'd. for C₂₅H₃₂N₅ (parent+1): 402.2658. Found: 402.2657.

EXAMPLE 1069-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-oxa-9-aza-bicyclo[3.3.1]non-7-ylamine

[0718] Prepared as in Example 1, usingN-t-butoxycarbonyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-ylamine in 9.5%yield, followed by removal of the t-butoxycarbonyl group usingtrifluoroacetic acid in methylene chloride at room temperature in 88%yield, as the hydrochloride salt.

[0719]¹H-NMR (CDCl₃, δ): 1.36 (m, 2H), 2.36 (m, 2H), 2.46 (bs, 2H), 2.70(m, 4H), 2.81 (m, 2H), 3.14 (m, 1H), 3.68 (m, 2H), 3.87 (m, 2H), 4.51(bs, 2H), 6.40 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.23 (m, 2H), 7.45 (t,J=8, 1H), 7.82 (m, 2H).

[0720]¹³C-NMR (CDCl₃, δ): 31.5, 34.5, 42.1, 51.4, 53.9, 69.8, 106.9,110.7, 126.7, 129.0, 137.6, 138.3, 140.9, 156.0, 158.0.

[0721] FAB MS (%): 339 (parent+1, 46), 322 (51), 197 (65), 149 (74), 119 (100), 103 (77), 98 (74).

[0722] Anal. Calc'd. for C₂₀H₂₆N₄O3HClH₂O{fraction (3/2)}(C₄H₁₀O): C54.12, H 8.04, N 9.71. Found: C 54.31, H 7.63, N 9.37.

[0723] HRMS Calc'd. for C₂₀H₂₇N₄O (parent+1): 339.2184. Found: 339.2155.

EXAMPLE 107{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine

[0724] Prepared as in Example 102, using ammonium formate andpalladium-on-carbon in refluxing ethanol in 87% yield, mp 170° C. (dec.)as the hydrochloride salt.

[0725]¹H-NMR (CDCl₃, δ): 1.36 (m, 2H), 2.09 (m, 2H), 2.79 (m, 2H), 2.91(m, 4H), 3.7-3.9 (m, 5H), 4.56 (bs, 2H), 6.36 (d, J=8, 1H), 7.01 (d,J=7, 1H), 7.23 (m, 2H), 7.42 (t, J=8, 1H), 7.81 (m, 2H).

[0726]¹³C-NMR (CDCl₃, δ): 36.4, 39.2, 47.7, 48.9, 50.5, 71.7, 106.9,110.6, 126.9,,128.9, 137.7, 138.3, 140.6, 155.9, 158.3.

[0727] MS (%): 339 (parent+1, 6), 167 (21), 149 (100), 129 (12), 113(31).

[0728] Anal. Calc'd. for C₂₀H₂₆N₄O3HCl{fraction (3/2)}H₂O: C 51.62, H7.29, N 10.94. Found: C 51.65, H 7.24, N 10.95.

EXAMPLE 108 6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine (cisdiastereomer)

[0729] A. N-Benzyl-2, 6-dimethylpiperidin-4-one: To a 500 mLround-bottomed flask equipped with condenser and N₂ inlet were added 40g (0.28 mol) 1, 3-acetonedicarboxylic acid, 24.8 g (0.64 mol)acetaldehyde, and 60 mL water. To the resulting mixture was added slowly30 mL (0.28 mol) benzyiamine over 30 minutes, the pH was adjusted to4-5, and the reaction stirred overnight at room temperature. Afterfiltration, the reaction pH was adjusted to 10 with 6 N sodiumhydroxide, and extracted with ethyl acetate. The organic layer waswashed with brine, dried, and evaporated, and the resulting residuechromatographed on silica gel using hexane/ethyl acetate as eluant toafford both isomers:

[0730] Trans isomer: 10.1 g (16.5%) oil.

[0731]¹H-NMR (CDCl₃, δ): 1.07 (d, J=7, 6H), 2.17 (m, 2H), 2.47 (m, 2H),3.25 (m, 2H), 3.75 (Ab_(q), J=14, Dn=110, 2H), 7.23 (m, 1H), 7.29 (m,2H), 7.37 (m, 2H).

[0732]¹³C-NMR (CDCl₃, δ): 17.4, 47.4, 51.3, 51.8, 126.9, 128.2, 128.3,140.2, carbonyl carbon not visible in this scan.

[0733] MS (%): 218 (parent+1, 100).

[0734] Cis isomer: 3.31 g (5.4%) oil.

[0735]¹H-NMR (CDCl₃, δ): 1.13 (d, J=6, 6H), 2.32 (m, 4H), 3.10 (m, 2H),3.83 (s, 2H), 7.21 (m, 1H), 7.30 (m, 2H), 7.39 (m, 2H).

[0736]¹³C-NMR (CDCl₃, δ): 21.5, 47.1, 50.0, 57.3, 126.5, 127.6, 128.2,141.0, carbonyl carbon not visible in this scan.

[0737] MS (%): 21 8 (parent+1, 100).

[0738] B. N-Benzyl-2, 6-dimethylpiperidin-4-one methoxime (cis isomer):To a 100 mL round-bottomed flask equipped with condenser and N₂ inletwere added 3.31 g (15.2 mmol) N-benzyi-2, 6-dimethylpiperidin-4-one, cisisomer, 2.1 g (24.3 mmol) methoxime hydrochloride, 3.4 mL (24.3 mmol)triethylamine, and 50 mL methanol. The reaction was refluxed 24 h,cooled, and evaporated. The residue was taken up in water/ethyl acetate,and the organic layer separated, washed with brine, dried, andevaporated. The residue was chromatographed on silica gel usinghexane/ethyl acetate to afford 1.5 g (40%) of an oil.

[0739]¹H-NMR (CDCl₃, δ): 1.10 (m, 6H), 1.92 (m, 1H), 2.11 (m, 1H), 2.29(m, 1H), 2.80 (m, 1H), 2.87 (m, 1H), 2.92 (m, 1H), 3.78 (s, 2H), 3.81(s, 3H), 7.19 (m, 1H), 7.28 (m, 2H), 7.36 (m, 2H).

[0740]¹³C-NMR (CDCl₃, δ): 16.5, 16.6, 31.6, 37.8, 49.65, 50.6, 52.3,61.1, 126.7, 128.2, 140.6, 157.3.

[0741] APCI MS (%): 247 (parent+1, 100),

[0742] C. N-Benzyl-2, 6-dimethylpiperidin-4-amine (cis isomer): To a 100mL round-bottomed flask equipped with condenser and N₂ inlet were added1.5 g (6.1 mmol) N-benzyl-2, 6-dimethylpiperidin-4-one methoxime (cisisomer), 60 mL dry tetrahydrofuran, and 15 mL (30 mmol) of a 2.0 Msolution of borane methyl sulfide in tetrahydrofuran. The reaction wasrefluxed 24 h, cooled, and the solvent evaporated. The residue wastreated with 60 mL ethanol, 1.9 g (18.3 mmol) sodium carbonate, and 1.5g cesium fluoride. The reaction was refluxed 24 h, cooled, andevaporated. The residue was taken up in water/ethyl acetate, and theorganic layer washed with brine, dried over sodium sulfate, andevaporated to afford 1.5 g (100%) of an oil.

[0743]¹H-NMR (CDCl₃, δ): 1.07 (d, J=6, 6H), 1.41 (m, 2H), 1.70 (m, 2H),2.56 (m, 2H), 2.66 (m, 1H), 3.77 (s, 2H), 7.17 (m, 1H), 7.25 (m, 2H),7.34 (m, 2H).

[0744]¹³C-NMR (CDCl₃, δ): 11.3, 2 1.7, 40.8, 44.4, 45.1, 48.5, 50.4,52.5, 126.4, 128.1, 128.2, 141.2.

[0745] MS (%): 219 (parent+1, 100).

[0746] D. N-Benzyl-2, 6-dimethylpiperidin-4-amine t-butylcarbamate (cisisomer): To a 100 mL round-bottomed flask equipped with condenser and N₂inlet were added 1.3 g (6.0 mmol) N-benzyl-2,6-dimethylpiperidin-4-amine (cis isomer), 1.3 g (6.0 mmol)di-t-butyl-dicarbonate, 1.2 mL (8.9 mmol) triethylamine, and 50 mLmethylene chloride. The reaction was stirred at room temperatureovernight, then washed with aqueous citric acid, water, and brine, driedover sodium sulfate, and evaporated. The residue was chromatographed onsilica gel using methylene chloride/ethyl acetate as eluant to afford1.6 g (84%) of an oil.

[0747]¹H-NMR (CDCl₃, δ): 1.05 (d, J=6, 6H), 1.13 (q, J=12, 2H), 1.42 (s,9H), 1.87 (m, 2H), 2.59 (m, 2H), 3.5 (bs, 1H), 3.76 (s, 2H), 4.3 (m,1H), 7.18 (m, 1H), 24 (m, 2H), 7.33 (m, 2H).

[0748]¹³C-NMR (CDCl₃, δ): 10.8, 21.6, 28.5, 37.6, 41.7, 44.2, 50.2,52.7, 79.0, 126.5, 128.1, 128.2, 141.0, 155.3.

[0749] APCI MS (%): 319 (parent+1, 100),

[0750] E. 2, 6-Dimethylpiperidin-4-amine t-butylcarbamate (cis isomer):To a 100 mL round-bottomed flask equipped with condenser and N₂ inletwere added 1.6 g (5.0 mmol) N-benzyl-2, 6-dimethylpiperidin-4-aminet-butylcarbamate (cis isomer), 2.5 g ammonium formate, 250 mg 10%palladium-on-carbon, and 40 mL ethanol. The reaction was refluxed 2 h,cooled, and filtered through Celite with ethanol and methylene chloride.The filtrate was evaporated, the residue was taken up in ethylacetate/water, the organic layer separated, washed with brine, driedover sodium sulfate, and evaporated to give a low-melting, white solid,1.09 g (95.5%).

[0751]¹H-NMR (CDCl₃, δ): 0.81 (q, J=11, 2H), 1.06 (d, J=6, 6H), 1.41 (s,9H), 1.91 (m, 2H), 2.72 (m, 2H), 3.5 (bs, 1H), 4.4 (m, 1H).

[0752]¹³C-NMR (CDCl₃, δ): 19.0, 22.8, 28.3, 37.5, 42.3, 43.7, 44.0,47.6, 78.9.

[0753] MS (%): 229 (parent+1, 62), 173 (100).

[0754] F2-(2, 5-Dimethylpyrrolyl)-6-((4-(4-t-butylcarboxamido-2,6-dimethylpiperidin-1-yl-carboxamido)methyl)phenyl))-pyridine: To a 100mL round-bottomed flask equipped with N₂ inlet were added 1.3 g (4.4mmol) 2-(2, 5-dimethylpyrrolyl)-6-((4-(carboxymethyl)phenyl))-pyridine,1.0 g (4.4 mmol) 2, 6-dimethylpiperidin-4-amine t-butylcarbamate (cisisomer), 1.7 g (8.8 mmol) N-ethyl-N-3-dimethylaminopropyl-carbodiimide,2.7 g (22 mmol) 4-dimethylaminopyridine, and 25 mL dimethylformamide.The reaction was stirred at room temperature for 24 h, taken up in ethylacetate/water, and the organic layc-r separated, washed with brine,dried over sodium sulfate, and evaporated. The residue waschromatographed on silica gel using hexane/ethyl acetate as eluant toafford 1.8 g (79%) of a foam.

[0755]¹H-NMR (CDCl₃, δ): 1.89 (m, 8H), 1.35 (s, 9H), 2.1 (m, 2H), 2.16(s, 6H), 3.4 (bs, 1H), 3.72 (s, 2H), 4.8 (m, 1H), 5.86 (s, 2H), 7.05 (d,J=8, 1H), 7.28 (m, 2H), 7.68 (d, J=8, 1H), 7.79 (t, J=8, 1H), 7.98 (m,2H).

[0756]¹³C-NMR (CDCl₃, δ): 13.4, 28.3, 35.6, 41.3, 44.1, 47.0, 60.2,79.1, 106.9, 118.1, 119.65, 127.1, 128.4, 128.9, 136.7, 138.5, 151.5,155.0, 156.4, 169.7.

[0757] APCI MS (%): 517 (parent+1, 65), 461 (100), 417 (32).

[0758] G. 2-(2, 5-Dimethylpyrrolyl)-6-((4-(4-amino-2,6-dimethylpiperidin-1-yl-carboxamido)methyl)phenyl))-pyridine: To a 100mL round-bottomed flask equipped with N₂ inlet were added 1.0 g (1.94mmol) 2-(2, 5-dimethylpyrrolyl)-6-((4-(6-t-butylcarboxamido-2,6-dimethylpiperidin-4-yl-carboxamidoamethyl)phenyl))-pyridine, 100 mLethyl acetate, and the solution cooled to 0° C. and saturated with HCl.The reaction was stirred 15 min at room temperature, evaporated, and theresidue taken up in 1 N sodium hydroxide solution and extracted withmethylene chloride. The organic layer was washed with brine, dried oversodium sulfate, and evaporated to give 770 mg (95.5%) of a foam.

[0759]¹H-NMR (CDCl₃, δ): 1.18 (m, 2H), 1.22 (d, J=7, 6H), 1.97 (m, 2H),2.15 (s, 6H), 2.68 (m, 1H), 3.72 (s, 2H), 4.3 (bs, 2H), 5.86 (s, 2H),7.06 (d, J=8, 1H), 7.27 (m, 2H), 7.66 (d, J=8, 1H), 7.79 (t, J=8, 1H),7.97 (m, 2H).

[0760]¹³C-NMR (CDCl₃, δ): 13.4, 24.3, 39.0, 41.6, 44.7, 47.1, 60.2,106.9, 118.1, 119.7, 127.1, 128.45, 128.9, 136.7, 136.9, 138.5, 151.5,156.3, 169.7.

[0761] MS (0% ): 417 (parent +1, 100).

[0762] H. 2-(2, 5-Dimethylpyrrolyl)-6-{4-[2-(4-amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridine (cis diastereomer):To a 100 mL three-necked round-bottomed flask equipped with condenser,septum and N2 inlet were added 640 mg (4.8 mmol) aluminum chloride, 20mL dry tetrahydrofuran, and after cooling to 0° C., 11.2 mL (11.2 mmol)of a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran.After stirring at 0° C. for 1 h, the reaction was cooled to −78° C., anda solution of 670 mg (1.6 mmol) 2-(2,5-dimethylpyrrolyl)-6-((4-(4-amino-2,6-dimethylpiperidin-1-yl-carboxamido)methyl)phenyl))-pyridine in 10 mLdry tetrahydrofuran added, and stirring continued at −78° C. for 1 h.The reaction was then warmed to room temperature and stirred overnight.The reactici was carefully quenched with dilute hydrochloric acid, thepH adjusted to 10 with 6 N sodium hydroxide solution, and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and evaporated. The residue was chromatographed onsilica gel using methanol/methylene chloride as eluant to give 423 mg(66%) of an oil.

[0763]¹H-NMR (CDCl₃, δ): 1.17 (m, 2H), 1.22 (d, J=6, 6H), 1.81 (m, 2H),1.95 (bs, 2H), 2.19 (s, 6H), 2.70 (m, 5H), 2.99 (m, 2H), 5.90 (s, 2H),7.08 (d, J=8, 1H), 7.22 (m, 2H), 7.68 (d, J=8, 1H), 7.81 (t, J=8, 1H),7.97 (m, 2H).

[0764]¹³C-NMR (CDCl₃, δ): 13.4, 21.0, 45.1, 48.1, 48.6, 49.4, 49.9,53.4, 106.9, 117.9, 119.5, 127.0, 158.5, 158.9, 136.1, 138.5, 142.2,151.5, 156.6.

[0765] MS (%): 403 (parent+1, 100).

[0766] I. 6-(4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine (cisdiastereomer): The deblocking was carried out using hydroxylaminehydrochloride as described in Example 124F to afford the product as anoil in 100% yield, which was converted to the hydrochloride salt as anamorphous solid.

[0767]¹H-NMR (CDCl₃, δ): 1.06 (m, 2H), 1.18 (d, J=6, 6H), 1.75 (m, 2H),2.63 (m, 5H), 2.95 (m, 2H), 4.58 (bs, 2H), 6.35 (d, J=8, 1H), 6.99 (d,J=8, 1H), 7.15 (m, 2H), 7.40 (t, J=8, 1H), 7.79 (m, 2H).

[0768]¹³C-NMR (CDCl₃, δ): 21.0, 45.3, 48.1, 48.6, 49.4, 53.4, 106.8,110.5, 126.8, 128.6, 137.4, 138.2, 141.1, 155.8, 158.2.

[0769] FAB MS (%): 325 (parent+1, 18), 149 (69), 119 (100).

[0770] HRMS Calc'd. for C₂₀H₂₉N₄ (parent+1): 325.2392. Found: 325.2369.

EXAMPLE 1096-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0771] Prepared as in Example 1, using N-methylpiperazine in 74% yield,mp 170° C. (dec.) as the hydrochloride salt.

[0772]¹H-NMR (CDCl₃, δ): 2.26 (s, 3H), 2.4-2.6 (broad multiplet, 8H),2.60 (m, 2H), 2.80 (m, 2H), 4.56 (bs, 2H), 6.35 (d, J=8, 1H), 7.00 (d,J=7, 1H), 7.23 (m, 2H), 7.41 (t, J=8, 1H), 7.80 (m, 2H).

[0773]¹³C-NMR (CDCl₃, δ): 33.3, 46.1, 53.1, 55.1, 60.3, 106.8, 110.6,126.8, 128.9, 137.6, 138.3,140.8, 156.0, 158.3.

[0774] FAB MS (°/0): 297 (parent+1, 100), 197 (28), 113 (73).

[0775] Anal. Calc'd. for C₁₈H₂₄N₄3HCl½H₂C. C 52.12, H 6.80, N 13.51.Found: C 52.05, H 7.00, N 13.07.

EXAMPLE 1106-{4-[2-(4-Benzenesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0776] Prepared as in Example 1, using N-benzenesulfonylpiperazine in93% yield, as the hydrochloride salt.

[0777]¹H-NMR (CDCl₃, δ): 2.60 (m, 6H), 2.74 (m, 2H), 3.04 (m, 4H), 4.64(bs, 2H), 6.44 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.20 (m, 2H), 7.48 (t,J=8, 1H), 7.52 (m, 3H), 7.73 (m, 2H), 7.81 (m, 2H).

[0778]¹³C-NMR (CDCl₃, δ): 33.0, 45.8, 51.9, 59.4, 106.9, 110.4, 126.7,127.6, 128.6, 128.8, 132.6, 135.0, 138.4, 140.0, 156.0, 158.0.

[0779] FAB MS (%): 423 (parent+1, 25), 1 67 (25), 149 (100), 113 (22).

[0780] Anal. Calc'd. for C₂₃H₂₆N₄O₂S2HCl{fraction (5/4)}H₂O: C 53.33, H5.94, N 10.82. Found: C 53.33, H 5.92, N 10.45.

EXAMPLE 1116-{4-[2-(4-Methanesulfonyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0781] Prepared as in Example 1, using N-methanesulfonylpiperazine in15% yield, as the hydrochloride salt.

[0782]¹H-NMR (CDCl₃, δ): 2.61 (m, 4H), 2.65 (m, 2H), 2.76 (s, 3H), 2.80(m, 2H), 3.23 (m, 4H), 4.49 (bs, 2H), 6.42 (d, J=8, 1H), 7.04 (d, J=7,1H), 7.23 (m, 2H), 7.46 (t, J =8, 1H), 7.83 (m, 2H).

[0783]¹³C-NMR (CDCl₃, δ): 33.1, 33.9, 45.8, 52.2, 59.6, 106.9, 110.6,126.8, 128.8, 137.6, 138.3, 140.3, 155.8, 158.1.

[0784] MS (%): 361 (parent+1, 17), 149 (100), 135 (54), 119 (89), 103(48).

[0785] Anal. Calc'd. for C₁₈H₂₄N₄O₂S2HCl: C 49.88, H 6.05, N 12.93.Found: C 50.1 1, H 6.08, N 11.69.

EXAMPLE 112 6-{4-[2-(2,6-Dimethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine: Refer toScheme 2:

[0786] A. 2-(2, 5-Dimethylpyrrolyl)-6-(4-formylphenyl)-pyridine: To a 1L round-bottomed flask equipped with condenser and N₂ inlet were added20.0 g (79.6 mmol) 6-bromo-2-(2, 5-dimethylpyrrolyl)-pyridine, 11.9 g(79.6 mmol) 4-formylphenyl boronic acid, 33.8 g (300 mmol) sodiumcarbonate, 1 g (0.8 mmol) tetrakis-triphenylphosphine palladium, 370 mLethanol, and 40 mL water. The mixture was refluxed 16 h, cooled, pouredinto water, and extracted into ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate, and evaporated. Theresidue was chromatographed on silica gel using hexane/ethyl acetate aseluant to afford 21.0 g (95.5%) of a light yellow, solid, mp 106-108° C.

[0787]¹H-NMR (CDCl₃, δ): 2.21 (s, 6H), 5.94 (s, 2H), 7.22 (d, J=8, 1H),7.82 (d, J=8, 1H), 7.93 (t, J=8, 1H), 7.98 (m, 2H), 8.22 (m, 2H), 10.07(s, 1H).

[0788]¹³C-NMR (CDCl₃, δ): 13.4, 107.2, 119.0, 120.9, 127.4, 128.6,130.1, 136.6. 138.8, 155.2, 191.9.

[0789] APCI MS (%): 277 (parent+1, 100).

[0790] B. 2-(2, 5-Dimethylpyrrolyl)-6-(4-(cyanomethyl)phenyl)-pyridine:To a 2 L round-bottomed flask equipped with condenser and N₂ inlet wereadded 17.1 g (152 mmol) potassium t-butoxide and 250 mL dry 1,2-dimethoxyethane (DME). The reaction was cooled to −60° C., and asolution of 16.2 g (83 mmol) tosylmethylisocyanide in 250 mL DME addeddropwise over 5 minutes. After stirring for 5 minutes, a solution of21.0 g (76 mmol) 2-(2, 5-dimethylpyrrolyl)-6-(4-formylphenyl)-pyridinein 500 mL DME was added dropwise over 10 minutes, and stirring continuedat −60° C. for 1 h. Then 250 mL methanol was added, and the reactionwarmed to room temperature, then refluxed 20 minutes. The reaction wascooled, evaporated, taken up in water and 8 mL acetic acid, andextracted with methylene chloride. The organic layer was washed withbrine, dried over sodium sulfate and evaporated. The residue waschromatographed with hexane/methylene chloride on silica gel to give 16.8 g (77%) of a low-melting solid.

[0791]¹H-NMR (CDCl₃, δ): 2.21 (s, 6H), 3.80 (s, 2H), 5.93 (s, 2H), 7.16(d, J=8, 1H), 7.42 (m, 2H), 7.74 (d, J=8, 1H), 7.89 (t, J=8, 1H), 8.08(m, 2H).

[0792] APCI MS (%): 287 (parent+1, 100).

[0793] C. 2-(2,5-Dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine: To a 2 Lround-bottomed flask equipped with condenser and N₂ inlet were added16.8 g (58.5 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-(cyanomethyl)phenyl)-pyridine and 500 mLethanol. The reaction was heated to reflux, and 1400 mL of a 10% aqueoussodium hydroxide solution added dropwise over 2 h. The reaction wasrefluxed an additional 2 h, cooled, and evaporated to a small volume,then the pH adjusted to 1 with concentrated hydrochloric acid(ice-cooling), and extracted into ethyl acetate. The organic layer waswashed with brine, dried over sodium sulfate, and evaporated to a lightyellow, low-melting solid, 16.9 g (94%).

[0794]¹H-NMR (CDCl₃, δ): 2.20 (s, 6H), 3.69 (s, 2H), 5.92 (s, 2H), 7.13(d, J=8, 1H), 7.37 (m, 2H), 7.72 (d, J=8, 1H), 7.86 (t, J=8, 1H), 8.03(m, 2H).

[0795]¹³C-NMR (CDCl₃, δ): 13.4, 40.7, 106.9, 118.2, 119.9, 127.1, 128.6,129.8, 134.5, 137.4, 138.6, 151.6, 156.3, 177.4.

[0796] APCI MS (%): 307 (parent+1, 100).

[0797] D. 2-(2, 5-Dimethylpyrrolyl)-6-(4-((2,6-dimethyl-4-t-butoxycarbonyl)piperazin-1-yl)methyl)phenyl)-pyridine: Toa 100 mL round-bottomed flask equipped with N₂ inlet were added 500 mg(1.6 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine, 350 mg (1.6mmol) 2, 6-dimethyl-4-t-butoxycarbonyl-piperazine, 626 mg (3.2 mmol)N-ethyl-N-3-dimethylaminopropyl-carbodiimide, 996 mg (8.1 mmol)4-dimethylamino-pyridine, and 10 mL dry dimethylformamide. The reactionwas stirred at room temperature for 16 h, poured into water, andextracted into ethyl acetate. The organic layer was washed with waterand brine, dried over sodium sulfate, and evaporated. The residue waschromatographed on solica gel using methanol/methylene chloride aseluant to afford 817 mg (100%) of a foam.

[0798]¹H-NMR (CDCl₃, δ): 1.23 (d, J=7, 6H), 1.44 (s, 9H), 2.19 (s, 6H),2.8 (m, 4H), 3.76 (m, 2H), 4.0 (m, 2H), 5.91 (s, 2H), 7.12 (d, J=8, 1H),7.33 (m, 2H), 7.72 (d, J=8, 1H), 7.85 (t, J=8, 1H), 8.01 (m, 2H).

[0799]¹³C-NMR (CDCl₃, δ): 13.4, 19.8, 21.0, 28.2, 40.8, 44.8, 46.9,48.1, 48.9, 79.9, 106.9, 118.1, 119.7, 127.2, 128.5, 128.9, 136.4,136.9, 138.5, 151.6, 155.2, 156.3, 169.8.

[0800] APCI MS (%): 503 (parent+1, 40), 447 (100), 403 (55).

[0801] E. 6-(4-((2,6-Dimethyl)piperazin-1-yl)methyl)phenyl)-pyridin-2-yl amine: 2-(2,5-Dimethylpyrroly1)-6-(4-((2,6-dimethyl-4-t-butoxycarbonyl)piperazin-1-yl)methyl)phenyl)-pyridine wasdeblocked first with hydroxylamine hydrochloride as described in Example1F, then with trifluoroacetic acid in methylene chloride as described inExample 2 to afford 455 mg (88% overall) of a foam.

[0802]¹H-NMR (CDCl₃, δ): 1.28 (d, J=7, 6H), 2.8 (m, 4H), 3.74 (s, 2H),4.55 (m, 2H), 6.43 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.30 (m, 2H), 7.47(t, J=8, 1H), 7.86 (m, 2 H).

[0803]¹³C-NMR (CDCl₃, δ): 40.5, 44.0, 48.2, 50.1, 107.2, 110.4, 126.9,128.7, 135.7, 138.0, 138.3, 155.3, 158.4, 170.0.

[0804] IR (KBr, cm.⁻¹): 1620 (C=0).

[0805] APCI MS (%): 325 (parent+1, 100).

[0806] F. 6-{4-[2-(2,6-Dimethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine: 6-(4-((2,6-Dimethyl)piperazin-1-yl)methyl)phenyl)-pyridin-2-yl amine was reducedwith borane methyl sulfide as described in Exmaple 124B to give an 8%yield of a hygroscopic solid as the hydrochloride salt.

[0807]¹H-NMR (CDCl₃, δ): 1.13 (d, 6H), 2.53 (m, 2H), 2.68 (m, 4H), 2.90(m, 2H), 3.00 (m, 2H), 4.49 (bs, 2H), 6.42 (d, J=8, 1H), 7.04 (d, J=7,1H), 7.19 (m, 2H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0808]¹³C-NMR (CDCl₃, δ): 17.6, 28.7, 49.8, 53.6, 54.2, 106.8, 110.6,126.9, 128.6, 137.5, 138.3, 141.1, 155.9, 158.1.

[0809] MS (%): 311 (parent+1, 14), 167 (23), 149 (100).

[0810] HRMS Calc'd. for C19H₂₇N₄: 311.2236. Found: 311.2236.

EXAMPLE 113 6-{4-[2-(2,6-Dimethyl-4-methylamino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0811] Prepared as in Example 112, using 4-t-butoxycarbonylamino-2,6-dimethylpiperidine coupling with 2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine in 75% yield,followed by reduction with borane methyl sulfide in refluxingtetrahydrofuran in 17% yield, followed by deprotection usinghydroxylamine hydrochloride in refluxing ethanol in 85% yield, as ahygroscopic solid as the hydrochloride salt.

[0812]¹H-NMR (CDCl₃, δ): 1.06 (m, 6H), 1.23 (m, 2H), 1.81 (m, 2H), 2.43(s, 3H), 2.53 (m, 1H), 2.7-2.9 (m, 6H), 4.51 (bs, 2H), 6.41 (d, J=8,1H), 7.03 (d, J=7, 1H), 7.24 (m, 2H), 7.45 (t, J=8, 1H), 7.82 (m, 2H).

[0813]¹³C-NMR (CDCl₃, δ): 11.4, 21.3, 32.4, 35.4, 36.6, 40.1, 48.7,50.8, 51.1, 52.0, 106.9, 110.7, 126.8, 129.0, 137.5, 138.3, 141.3,156.1, 158.2.

[0814] APCI MS (%): 339 (parent+1, 100).

[0815] Anal. Calc'd. for C₂₁H₃₀N₄3HCl½CH₂Cl₂{fraction (9/4)}(C₄H₁₀O): C55.75, H 8.67, N 8.53. Found: C 55.66, H 8.21, N 8.02.

EXAMPLE 1146-{4-[2-(4-Cyclohexyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0816] Prepared as in Example 112, using N-cyclohexylpiperazine couplingwith 2-(2, 5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine in100% yield followed by reduction using borane methyl sulfide inrefluxing tetrahydrofuran in 97% yield, then deprotection usinghydroxylamine hydrochloride in refluxing ethanol in 98% yield, as thehydrochloride salt.

[0817]¹H-NMR (CDCl₃, δ): 1.09 (m, 6H), 1.75 (m, 2H), 1.88 (m, 2H), 2.24(m, 1H), 2.59 (m, 10H), 2.83 (m, 2H), 4.53 (bs, 2H), 6.38 (d, J=8, 1H),7.02 (d, J=8, 1H), 7.22 (m, 2H), 7.43 (t, J=8, 1H), 7.81 (m, 2H).

[0818]¹³C-NMR (CDCl₃, δ): 25.5, 25.9, 28.5, 33.0, 48.5, 53.2, 60.0,63.1, 106.5, 110.3, 126.4, 128.5, 137.2, 137.9, 140.5, 155.6, 157.8.

[0819] APCI MS (%): 365 (parent+1, 100).

[0820] Anal. Calc'd. for C₂₃H₃₂N₄3HCl¼H₂O¼(C₄H₁₀O)¼CH₂Cl₂: C 56.21, H7.49, N 10.81. Found: C 56.12, H 7.83, N 10.44.

EXAMPLE 1156-{4-[2-(Adamantan-1-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0821] Prepared as in Example 112, using 1-aminoadamantane for thecoupling with 2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine followed bydeblocking with hydroxylamine hydrochloride and borane methyl sulfidereduction in 89.5% yield, mp 200-220° C. (dec.) as the hydrochloridesalt.

[0822]¹H-NMR (CDCl₃, δ): 1.58 (bs, 12H), 2.02 (bs, 3H), 2.80 (m, 2H),2.85 (m, 2H), 4.54 (bs, 2H), 6.40 (d, J=8, 1H), 7.03 (d, J=7, 1H), 7.25(m, 2H), 7.45 (t, J=8, 1H), 7.83 (m, 2H).

[0823]¹³C-NMR (CDCl₃, δ): 29.6, 36.7, 36.8, 41.7, 42.6, 50.5, 106.9,110.7, 126.9, 128.9, 137.7, 138.3, 140.7, 156.0, 158.3.

[0824] FAB MS (%): 348 (parent+1, 44), 135 (100).

[0825] Anal. Calc'd. for C₂₃H₂₉N₃2HCl{fraction (3/2)}H₂O½(C₄H₁₀O): C61.98, H 8.11, N 8.67. Found: C 61.95, H 7.90, N 8.69.

EXAMPLE 1166-{4-[2-(Adamantan-2-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0826] Prepared as in Example 112, using 2-aminoadamantane for thecoupling with 2-(2,5-dimethylpyrrolyl)-6-(4-(carboxymethyl)phenyl)-pyridine followed bydeblocking with hydroxylamine hydrochloride and borane metniyl sulfidereduction in 98% yield, mp 215-230° C. (dec.) as the hydrochloride salt.

[0827]¹H-NMR (CDCl₃, δ): 1.43 (m, 2H), 1.67 (bs, 4H), 1.81 (m, 8H), 2.72(bs, 1H), 2.85 (m, 4H), 4.53 (bs, 2H), 6.40 (d, J=8, 1H), 7.04 (d, J=7,1H), 7.26 (m, 2H), 7.45 (t, J=8, 1H), 7.83 (m, 2H).

[0828]¹³C-NMR (CDCl₃, δ): 27.5, 27.8, 31.3, 32.0, 37.6, 37.9, 48.1,106.8, 110.7, 126.8, 128.9, 137.6, 138.3, 141.0, 156.1, 158.2.

[0829] FAB MS (%): 348 (parent+1, 80), 135 (100).

[0830] Anal. Calc'd. for C₂₃H₂₉N₃2HCl{fraction (7/4)}H₂O¾(C₄H₁₀O): C61.53, H 8.34, N 10 8.28. Found: C 61.55, H 8.12, N 8.01.

EXAMPLE 117 6-{4-[2-(Indan-2-ylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0831] A. 6-(4-(2-Aminoethyl)phenyl-2-(2, 5-dimethylpyrrolyl)pyridine:To a 250 mL round-bottomed flask equipped with condenser and N2 inletwere added 3.04 g (10.59mmol)6-(4-(cyanomethyl)phenyl-2-(2,5-dimethylpyrrolyl)pyridine, 100mL dry tetrahydrofuran, and 53 mL (53mmol) of a 1.0 M solution of lithium aluminum hydride intetrahydrofuran. The reaction was refluxed 40 h, with 20 mL lithiumaluminum hydride reagent solution added after 24 h, cooled, and quenchedcarefully with water. The mixture was taken up in 0.5 N aqueous sodiumhydroxide solution and ethyl acetate, and the organic layer was washedwith water, then extracted with hydrochloric acid. The aqueous layer waswashed with water, then adjusted to pH 10 with aqueous sodium hydroxidesolution and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, and evaporated to an oil, 1.37 g(43%), which was used without further purification.

[0832]¹H-NMR (d, CDCl₃): 1.6 (broad, 2H), 2.20 (s, 6H), 2.80 (m, 2H),2.99 (m, 2H), 5.91 (s, 2H), 7.10 (d, J=8, 1H), 7.28 (m, 2H), 7.70 (m,1H), 7.84 (m, 1H), 7.98 (m, 2H).

[0833] MS (APCI) (%): 292 (100, parent+1).

[0834] B. 6-{4-[2-(Indan-2-ylamino)-ethyyl-phenyl}-pyridin-2-ylamine

[0835] Prepared from the above oil by reductive amination with2-indanone using sodium cyanoborohydride in methanol at room temperaturein 17% yield, followed by deblocking with hydroxylamine hydrochloride inrefluxing ethanol in 82.5% yield, mp 60-70° C. (dec.) as thehydrochloride salt.

[0836]¹H-NMR (CDCl₃, δ): 2.72 (AB pattern, 2H), 2.91 (ddd, J=6.6, 7, 38,4H), 3.14 (AS pattern, 2H), 3.64 (quintet, J=7, 1H), 4.56 (bs, 2H), 6.40(dd, J=0.4, 8, 1H), 7.04 (dd, J=0.6, 7, 1H), 7.15 (m, 4H), 7.27 (m, 2H),7.46 (dt, J=0.4, 8, 1H), 7.85 (m, 2H).

[0837]¹³C-NMR (CDCl₃, δ): 36.1, 39.9, 49.4, .59.5, 107.0, 110.8, 124.7,126.4, 127.0, 128.9, 137.8, 138.4, 140.4, 141.5, 156.0, 158.3.

[0838] FAB MS (%): 330 (parent+1, 100), 197 (42), 132, (43), 117 (80).

[0839] Anal. Calc'd. for C₂₂H₂₃N₃ 2HCl2H₂O: C 60.27, H 6.67, N 9.58.Found: C 60.35T H 6.48, N 1 0.00.

EXAMPLE 118 6-(4-(2-Aminoethyl)phenyl-pyridin-2-ylamine

[0840] Prepared byde blocking Example 117A above using hydroxylaminehydrochloride in refluxing ethanol in 56% yield, mp 73-83° C. (dec.) asthe hydrochloride salt.

[0841]¹H-NMR (DMSO-d₆, δ): 2.95 (m, 2H), 3.02 (m, 2H), 4.0 (bs, 4H),6.96 (d, J=9, 1H), 7.21 (d, J=7, 1H), 7.45 (m, 2H), 7.8-8.0 (m, 3H).

[0842]¹³C-NMR (DMSO-d₆, δ): 25.4, 32.8, 40.4, 67.8, 110.0, 111.8, 127.5,129.9, 140.3, 143.8, 146,3, 155.3.

[0843] FAB MS (%): 214 (parent+1, 54), 135 (49), 119 (100), 103 (49).

[0844] HRMS Calc'd. for C₁₃H₁₆N₃ (parent+1): 214.1 344. Found: 214.1 351.

EXAMPLE 1196-{4-[2-(Bis-pyridin-3-ylmethyl-amino)-ethyl]-phenyl}-pyridin-2-ylamine

[0845] Prepared from Example 117A by reductive amination withpyridine-3-carboxaldehyde using sodium cyanoborohydride in methanolfollowed by deblocking using hydroxylamine hydrochloride in refluxingethanol in 63% yield as a hygroscopic solid as the hydrochloride salt.

[0846]¹H-NMR (CDCl₃, δ): 2.72 (m, 2H), 2.83 (m, 2H), 3.61 (s, 4H), 6.46(d, J=8, 1H), 6.97 (d, J=7, 1H), 7.09 (m, 2H), 7.17 (m, 2H), 7.47 (t,J=8, 1H), 7.54 (m, 2H), 7.74 (m, 2H), 8.41 (m, 4H).

[0847]¹³C-NMR (CDCl₃, δ): 29.7, 53.4, 54.9, 107.7, 110.6, 123.6, 126.9,129.0, 134.8, 136.6, 139.1, 140.9, 148.3, 149.6, 154.8, 158.0.

[0848] MS (%): 396 (parent+1, 100).

[0849] HRMS Calc'd. for C₂₅H₂₆N₅ (parent+1): C 396.2188. Found:396.2155.

EXAMPLE 1206-{4-[2-(Bis-pyridin-4-ylmethyl-amino)-ethyl]-phenyl}-pyridin-2-ylamine

[0850] Prepared as in Example 119, using pyridine-4-carboxaldehyde, in75% yield, mp 150-163° C. (dec.) as the hydrochloride salt.

[0851]¹H-NMR (CDCl₃, δ): 2.70 (m, 2H), 2.81 (m, 2H), 3.60 (s, 4H), 6.42(d, J=8, 1H), 7.03 (d, J=7, 1H), 7.06 (m, 2H), 7.16 (m, 4H), 7.46 (t,J=8, 1H), 7.81 (m, 2H), 8.46 (m, 4H). ¹³C-NMR (CDCl₃, δ): 33.4, 55.4,57.3, 107.0, 110.6, 123.3, 126.7, 128.9, 137.7, 138.3, 140.3, 148.4,149.7, 155.7, 158.2.

[0852] MS (%): 396 (parent+1, 100).

[0853] HRMS. Calc'd. for C₂₅H₂₆N₅ (parent+1): C 396.2188. Found:396.2152.

EXAMPLE 121N-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-N-(1-benzyl-piperidin-4-yl)-acetamide

[0854] Prepared as in Example 117, using N-benzyl-4-piperidone withsodium cyanoborohydride in methanol, followed by acetylation with acetylchloride and triethylamine in methylene chloride, followed by deblockingwith hydroxylamine hydrochloride in refluxing ethanol in 44% yield, mp60-70° C. (dec.) as the hydrochloride salt.

[0855]¹H-NMR (CDCl₃, δ): 1.8-1.9 (m, 4H), 2.12 (s, 3H), 2.84 (m, 2H),2.96 (m, 2H), 3.40 (m, 4H), 3.50 (s, 2H), 4.59 (bs, 2H), 6.42 (t, J=8,1H), 7.02 (d, J=7, 1H), 7.2-7.4 (m, 7H), 7.45 (dt, J=7,8, 1H), 7.82 (m,2H).

[0856]¹³C-NMR (CDCl₃, δ): 14.2, 14.7, 22.1, 22.2, 30.0, 30.8, 35.5,37.6, 43.8, 46.0, 53.0, 53.1, 62.9, 63.0, 107.1, 107.2, 110.8, 126.9,128.1, 128.2, 128.7, 128.9, 129.2, 129.3, 137.0, 137.7, 137.8, 138.3,138.4, 138.6, 140.2, 155.7, 156.1, 158.2, 158.3, 170.2, 170.7.

[0857] FAB MS (%): 429 (parent+1, 44), 91 (100).

[0858] HRMS Calc'd. for C₂₇H₃₃N₄O (parent+1): C 429.2654. Found:429.2669.

EXAMPLE 1226-[4-(4-Methyl-piperazin-1-ylmethyl)-phenyl-pyridin-2-ylamine

[0859] Prepared from (6-(4-formylphenyl)2-(2,5-dimethylpyrrolyl)-pyridine (Example 112), using N-methylpiperazinewith sodium cyanoborohydride in methanol in 43% yield, followed bydeblocking using hydroxylamine hydrochloride in refluxing ethanol in 78%yield, mp 240-250° C. (dec.) as the hydrochloride salt.

[0860]¹H-NMR (CDCl₃, δ): 2.24 (s, 3H), 2.4 2.5 (m, 8H), 3.49 (s, 2H),4.66 (bs, 2H), 6.36 (d, J=8, 1H), 7.00 (d, J=7, 1H), 7.34 (m, 2H), 7.41(t, J=8, 1H), 7.81 (m, 2H).

[0861]¹³C-NMR (CDCl₃, δ): 46.0, 53.0, 55.1, 62.7, 107.0, 110.7, 126.7,129.4, 138.3, 138.6, 156.0, 158.4.

[0862] FAB MS (%): 283 (parent+1, 82), 244 (45), 183 (100).

[0863] Anal. Calc'd. for C₁₇H₂₂N₄3HCl2H₂O: C 47.73, H 6.83, N 13.10.Found: C 47.85, H 6.78, N 12.92.

EXAMPLE 1233-[4-(6-Amino-pyridin-2-yl)-benzyl]-3-aza-bicyclo[3.1.0]hex-6-ylamine

[0864] Prepared as in Example 122, using6-(t-butoxycarbonylamino)-3-aza-bicyclo[3.1.0]hexane in the reductiveamination in 66% yield, and in 75% yield for the deblocking whichincluded trifluoroacetic acid in methylene chloride to remove thet-butoxycarbonyl group, mp 189-192° C. (dec.) as the hydrochloride salt.

[0865]¹H-NMR (CDCl₃, δ): 1.28 (bs, 2H), 2.34 (m, 2H), 2.51 (bs, 1H),2.85 (m, 2H), 3.48 (s, 2H), 3.61 (bs), 6.38 (d, J=8, 1H), 6.90 (d, J=7,1H), 7.23 (m, 2H), 7.39 (t, J=8, 1H), 7.66 (m, 2H).

[0866]¹³C-NMR (MeOD₄, δ): 25.2, 32.1, 54.4, 58.9, 107.3, 110.9, 126.7,128.8, 138.4, 138.5, 139.4, 156.0, 158.5.

[0867] FAB MS (%): 281 (parent+1, 97), 212 (30), 183 (100).

[0868] Anal. Calc'd. for C₁₇H₁₉N₄3HCl½H₂O: C 70.56, H 7.31, N 19.36.Found: C 70.76, H 7.15, N 19.17.

EXAMPLE 1246-{4-[2-(Bis-cyclohexylmethyl-amino)-ethyl]-phenyl}-pyridin-2-ylamine:refer to Scheme 2

[0869] A. N,N-Dibenzyl(4-bromophenyl)acetamide: To a 100 mLround-bottomed flask equipped with N₂ inlet were added 1.075 g (5 mmol)4-bromophenylacetic acid, 0.961 mL (5 mmol) dibenzylamine, 20 mL dryacetonitrile, 10 mg 1-hydroxybenzotriazole, 959 mg (5 mmol) EDAC, and1.74 mL (12.5 mmol) triethylamine. The reaction was stirred at roomtemperature for 36 hr, poured into aqueous sodium bicarbonate solution,and extracted into ethyl acetate. The organic layer was washed withwater aqueous citrate, water, and brine, dried over sodium sulfate, andevaporated to give 2.0 g (100%) of an oil which was used directly.

[0870]¹H-NMR (CDCl₃, δ): 3.705 (s, 2H), 4.43 (s, 2H), 4.61 (s, 2H),7.1-7.4 (m, 14H).

[0871]¹³C-NMR (CDCl₃, δ): 40.1, 48.5, 50.2, 120.9, 126.3, 127.5, 127.8,128.3, 128.6, 129.1, 130.7, 130.8, 131.7, 134.0, 136.2, 137.1, 171.1.

[0872] MS (%): 393/395 (parent+1, 98/100).

[0873] B. N,N-Dibenzyl-2-(4-bromophenyl)ethaneamine: To a 100 mLround-bottomed flask equipped with condenser and N₂ inlet were added theabove oil (5 mmol), 25 mL dry tetrahydrofuran, and 7.5 mL (15 mmol) of a2.0 M solution of borane,methyl sulfide in tetrahydrofuran. The reactionwas refluxed 18 hr, cooled, and evaporated. The residue was taken up in25 mL ethanol, and treated with 1 g sodium carbonate and 1 g cesiumfluoride, then refluxed 18 hr. The reaction was cooled, evaporated, andthe residue taken up in water/ethyl acetate. The organic layer wasseparated, washed with water and brine, dried over sodium sulfate, andevaporated. The resulting oil (1.75 g, 92%) was used directly.

[0874]¹H-NMR (CDCl₃, δ): 2.70 (m, 2H), 2.75 (m, 2H), 3.65 (s, 4H), 6.95(d, J=8, 1H), 7.2-7.4 (m, 13H).

[0875]¹³C-NMR (CDCl₃, δ): 33.0, 54.8, 58.3, 119.6, 126.9, 128.2, 128.7,130.7, 131.2, 139.563, 139.635.

[0876] MS (%): 380/382 (parent+1, 9 5/1 00).

[0877] C. 2-(2,5-Dimethylpyrrol-1-yl)-6-(4-(2-(N,N-dibenzylamino)ethyl)phenyl)-pyridine:To a 100 mL three-necked round-bottomed flask equipped with septum andN2 inlet were added 1.75 g (4.60 mmol) ofN,N-dibenzyl-2-(4-bromophenyl)ethaneamine and 16 mL dry ether. Thesolution was cooled to −70° C., and 3.45 mL of a 1.6 M solution (5.53mmol) of butyl lithium in hexanes added dropwise over 5 min. Thereaction was stirred 5 min at −70° C., then warmed to room temperature,and a solution of 0.950 g (5.53 mmol) 2-(2,5-dimethylpyrrol-1-yl)-pyridine in 5 mL dry ether added over 3 min. Thereaction turned to dark orange and then dark red as it was stirred atroom temperature for 6 hr, then quenched with aqueous ammonium chloride.The organic layer was diluted with ethyl acetate and separated, washedwith aqueous ammonium chloride and brine, dried over sodium sulfate for14 hr in the air (to permit air oxidation to the pyridine) andevaporated. The residue was chromatographed on silica gel using 10%ethyl acetate in hexane as eluant to afford the product as an oil, 860mg (40%).

[0878]¹H-NMR (CDCl₃, δ): 2.45 (s, 6H), 2.9-4 (m, 2H), 3.04 (m, 2H), 3.84(s, 4H), 6.18 (s, 2H), 7.24 (d, J=8, 1H), 7.3-7.5 (m, 12H), 7.83 (d,J=8, 1H), 7.92 (t, J=8, 1H), 8.17 (m, 2H).

[0879]¹³C-NMR (CDCl₃, δ): 13.8, 33.5, 55.1, 58.5, 107.3, 118.2, 119.7,127.0, 128.4, 128.8, 128.9, 129.1, 129.5, 138.7, 139.85, 142.4, 151.8,157.0.

[0880] MS (%): 472 (parent+1, 100).

[0881] D. 2-(2,5-Dimethylpyrrol-1-yl)-6-(4-(2-aminoethyl)phenyl)-pyridine: To a 100 mLthree-necked round-bottomed flask equipped with septum and N2 inlet wereadded 860 mg (1.826 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-(N,N-dibenzylamino)ethyl)phenyl)-pyridine,576 mg (9.13 mmol, 5 eq.) ammonium formate, 20 mL ethanol, and 100 mg10% Pd-C. The reaction was refluxed 2 hr, and additional portion ofammonium formate and palladium added, and refluxing continued another 1hr. The cooled reaction was filtered through Celite using ethanol andmethylene chloride, and the filtrate evaporated. The residue was takenup in aqueous sodium bicarbonate solution and ethyl acetate, the aqueouslayer reextracted with ethyl acetate, and the organic layer separatedand washed with brine, dried over sodium sulfate, and evaporated. Thecrude oil, 430 mg (81 %) was used directly.

[0882]¹H-NMR (CDCl₃, δ): 2.20 (s, 6H), 2.4 (bs, 2H), 2.80 (m, 2H), 2.98(m, 2H), 5.91 (s, 2H), 7.09 (d, J=8, 1H), 7.26 (m, 2H), 7.69 (d, J=8,1H), 7.82 (t, J=8, 1H), 7.99 (m, 2H).

[0883]¹³C-NMR (CDCl₃, δ): 14.2, 39.3, 43.2, 60.4, 106.9, 118.1, 119.7,127.0, 129.3, 136.5, 138.6, 141.0, 151.6, 156.7.

[0884] MS (%): 292 (parent+1, 100).

[0885] E. 2-(2,5-Dimethylpyrrol-1-yl)-6-{4-[2-(bis-cyclohexylmethyl-amino)-ethyl]-phenyl}-pyridine:To a 100 mL round-bottomed flask equipped with N₂ inlet were added 215mg (0.739 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-aminoethyl)phenyl)-pyridine, 179 uL (1.48mmol) cyclohexanecarboxaldehyde, 7 mL methanol, and 93 mg (1.48 mmol)sodium cyanoborohydride. The reaction was stirred at room temperaturefor 18 h, poured into dilute aqueous sodium bicarbonate solution, andextracted into ethyl acetate. The organic layer was washed with waterand brine, dried over sodium sulfate, and evaporated. The residue waschromatographed on silica gel using ethyl acetate/hexane as eluant toafforu the product, 134 mg (37.5%) as an oil.

[0886]¹H-NMR (CDCl₃, δ): 0.84 (m, 4H), 1.20 (m, 6H), 1.40 (m, 2H), 1.69(m, 6H), 1.78 (m, 2H), 2.2 (m, 6H), 2.24 (s, 6H), 2.63 (m, 2H), 2.76 (m,2H), 5.96 (s, 2H), 7.12 (d, J=8, 1H), 7.30 (m, 2H), 7.73 (d, J=8, 1H),7.85 (t, J=8, 1H), 8.01 (m, 2H).

[0887]¹³C-NMR (CDCl₃, δ): 13.5, 26.3, 27.0, 31.9, 33.5, 36.4, 57.2,62.4, 106.9, 118.0, 119.5, 126.8, 128.7, 129.3, 135.9, 138.5, 143.0,151.6, 157.0.

[0888] PAS (%): 484 (parent+1, 100).

[0889] F.6-{4-[2-(Bis-cyclohexylmethyl-amino)-ethyl]-phenyl}-pyridin-2-ylamine:To a 100 mL round-bottomed flask equipped with condenser and N₂ inletwere added 134 mg (0.277 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-{4-[2-(bis-cyclohexylmethyl-amino)-ethyl]-phenyl}-pyridine,96 mg (1.387 mmol) hydroxylamine hydrochloride, 1 mL water and 5 mLethanol. The solution was heated at 80° C. for 35 h, cooled, and pouredinto dilute aqueous hydrochloric acid. The aqueous layer washed withethyl acetate, the pH adjusted to 11 with 1 N sodium hydroxide solution,arid extracted with ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, and evaporated. The resulting oil wastaken up in ether and precipitated using 1 N HCl in ether. The productwas collected as a tan solid, mp 75-85° C., 68 mg (51%).

[0890]¹H-NMR (CDCl₃, δ): 0.81 (m, 6H), 1.24 (m, 6H), 1.38 (m, 2H), 1.66(m, 6H), 1.74 (m, 2H), 2.17 (d, J=7, 4H), 2.60 (m, 2H), 2.70 (m, 2H),4.55 (bs, 2H), 6.40 (d, J=8, 1H), 7.04 (d, J=7, 1H), 7.23 (m, 2H), 7.45(t, J=8, 1H), 7.81 (m, 2H).

[0891]¹³C-NMR (CDCl₃, δ): 26.3, 27.0, 31.9, 33.4, 36.4, 57.2, 62.4,106.8, 110.7, 126.7, 129.0, 137.2, 138.3, 142.0, 156.2, 158.3.

[0892] MS (%): 406 (parent+1, 100).

[0893] Anal. Calc'd. for C₂₇H₃₉N₃2HCl2H₂O: C 63.02, H 8.81, N 8.17.Found: C 62.54, H 8.92, N 8.56.

EXAMPLE 1256-{4-[2-(4-Phenyl-butylamino)-ethyl]-phenyl}-pyridin-2-ylamine:

[0894] A. N-(2-(2,5-Dimethylpyrrol-1-yl)-6-ethyl]-phenyl}-pyridyl)-(3-phenylbutyramide):To a 100 mL round-bottomed flask equipped with N₂ inlet were added 200mg (0.687 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2-aminoethyl)phenyl)-pyridine (Example100D), 113 mg (0.687 mmol) 3-phenylbutyric acid, 132 mg (0.687 mmol)EDAC, 10 mg N-hydroxybenzot-iazole, 5 mL dry acetonitrile, and 211 uL(1.51 mmol) triethylamine. The reaction was stirred at room temperaturefor 12 h, poured into dilute aqueous citrate solution, and extractedinto ethyl acetate. The organic layer was washed with water, aqueoussodium bicarbonate solution, and brine, dried over sodium sulfate, andevaporated. The resulting yellow oil, 300 mg (100%) was used directly.

[0895]¹H-NMR (CDCl₃, δ): 1.28 (m, 2H), 2.23 (s, 6H), 2.61 (m, 2H), 2.85(m, 4H), 3.51 (m, 2H), 5.95 (s, 2H), 7.1-7.4 (m, 8H), 7.70 (d, J=8, 1H),7.85 (t, J=8, 1H), 8.00 (m, 2H).

[0896]¹³C-NMR (CDCl₃, δ): 13.5, 27.1, 35.2, 35.5, 35.8, 40.4, 107.0,118.2, 119.8, 125.9, 127.2, 128.4, 128.5, 128.6, 129.2, 136.7, 138.0,140.5, 141.5, 151.7, 156.6, 172.8.

[0897] MS (%): 438 (parent+1, 100).

[0898] B2-(2, 5-Dimethylpyrrol-1-yl)-6-{4-[2-(4-phenylbutyl)-ethyl]-phenyl}-pyridine: To a 100 mLround-bottomed flask equipped with condenser and N₂ inlet were added 300mg (0.687 mmol) N-(2-(2,5-dimethylpyrrol-1-yl)-6-ethyl]-phenyl}-pyridyl)-(3-phenylbutyramide),10 mL dry tetrahydrofuran, and 1.0 mL (2.06 mmol) of a 2.0 M solution ofborane methyl sulfide in tetrahydrofuran. The reaction was refluxed 20h, cooled, and evaporated. The residue was taken up in 40 mL ethanol,treated with 1 g sodium carbonate and 0.5 g cesium fluoride, andrefluxed 40 h. The reaction was cooled and evaporate, and the residuetaken up in ethyl acetate/water. The organic layer was separated, washedwith water and brine, dried over sodium sulfate, and evaporated. Theresidue was chromatographed on silica gel using methanol/methylenechloride as eluant to afford the product as a low-melting solid, 13 mg(4.5 %).

[0899]¹H-NMR (CDCl₃, δ): 1.67 (m, 2H), 1.97 (m, 2H), 2.18 (s, 6H), 2.58(m, 2H), 2.93 (m, 2H), 3.14 (m, 2H), 3.25 (m, 2H), 5.91 (s, 2H), 7.1-7.3(m, 8H), 7.66 (d, J=8, 1H), 7.82 (t, J=8, 1H), 7.96 (m, 2H).

[0900]¹³C-NMR (CDCl₃, δ): 13.4, 26.1, 28.6, 33.8, 35.3, 47.9, 49.0,107.0, 118.2, 119.9, 126.0, 127.4, 128.3, ;28.4, 129.1, 138.2, 138.6,141.4,. 151.7, 156.4.

[0901] MS (%): 424 (parent+1, 100).

[0902] C. 6-{4-[2-(4-Phenyl-butylamino)-ethyl]phenyl}-pyridin-2-ylamine:To a 100 mL round-bottomed flask equipped with condenser and N₂ inletwere added 13 mg (0.0307 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-{4-[2-(4-phenylbutyl)-ethyl]-phenyl}-pyridine,21 mg (0.307 mmol) hydroxylamine hydrochloride, 4 mL ethanol, and 1 mLwater. The reaction was refluxed 40 h, cooled, and poured into water andextracted into ethyl acetate. The organic layer was separated, washedwith water and brine, dried over sodium sulfate, and evaporated. Theresidue was taken up in ether and precipitated with 1 N HCl in ether toafford a hygroscopic solid, 3 mg (23%).

[0903]¹H-NMR (CDCl₃, δ): 1.49 (m, 2H), 1.59 (m, 2H), 2.59 (m, 4H), 2.84(m, 4H), 4.54 (bs, 2H), 6.42 (d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.14 (m,2H), 7.24 (m, 5H), 7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0904]¹³C-NMR (CDCl₃, δ): 29.1, 29.6, 35.8, 35.9, 49.6, 50.9, 106.9,110.8, 125.6, 126.9, 127.1, 128.2, 128.4, 128.9, 138.3, 140.5, 142.4,156.1, 158.2.

[0905] MS (%): 346 (parent+1, 100).

EXAMPLE 1266-{4-[2-(5-Phenyl-pentylamino)-ethyl]-phenyl}-pyridin-2-ylamine

[0906] Prepared as in Example 100A, using 4-phenyl pentanoic acid, witha 45% yield in the final step, as a solid, mp 60-70° C.

[0907]¹H-NMR (CDCl₃, δ): 1.31 (m, 2H), 1.50 (m, 2H), 1.60 (m, 2H), 2.58(m, 4H), 2.87 (m, 4H), 4.49 (bs, 2H), 6.42 (d, J =8, 1 H), 7.04 (d, J=7,1H), 7.14 (m, 2H), 7.24 (m, 5H), 7.47 (t, J=8, 1H), 7.83 (m, 2H).

[0908]¹³C-NMR (CDCl₃, δ): 26.9, 29.6, 31.3, 35.8, 49.6, 50.9, 106.9,110.7, 125.6, 126.9, 128.2, 128.4, 128.9, 137.8, 138.3, 142.6, 158.2.

[0909] MS (%): 360 (parent+1, 100).

EXAMPLE 127 6-{4-[3-(1, 2, 3,4-Tetrahydro-naphthalen-2-ylamino)-propyl]-phenyl}-pyridin-2-ylamine

[0910] Prepared using 2-(2,5-dimethylpyrrol-1-yl)-6-(4-(3-aminopropyl)phenyl)-pyridine, which wasprepared as in Example 100, starting from 3-(4-bromophenyl)-propionicacid, which was prepared as follows: To a 500 mL round-bottomed flaskequipped with addition funnel and N₂ inlet were added 45 mL formic acid,which was cooled to 0° C., followed by dropwise addition of 67 mLtriethylamine. The resulting solution was warmed to room temperature,followed by addition of 9.25 g (50 mmol) of 4-bromobenzaldehyde and 7.21g (50 mmol) of Meldrum's acid. The reaction was heated to 95° C. over 1h, then heated at 91-100° C. for 2 h. The reaction was cooled, pouredinto ice/water, and the pH adjusted to 1 with 6 N hydrochloric acid. Themixture was let stand at 0° C. for 14 h, and the precipitate collected,washed with water, and taken up in ethyl acetate and extracted withaqueous sodium bicarbonate solution. The aqueous layer was washed withethyl acetate, then the pH adjusted to 1 with 6 N hydrochloric acidfollowed by extraction with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, and evaporated to a solid, 4.56 g(40%).

[0911]¹H-NMR (CDCl₃, δ): 2.66 (t, J=7, 2H), 2.92 (t, J=7, 2H), 7.1 (m,2H), 7.45 (m, 2H).

[0912]¹³C-NMR (CDCl₃, δ): 29.9, 35.3, 120.2, 130.0, 131.6, 139.0, 178.8.

[0913] The remaining steps were carried out following Example 124 tomake 2-(2,5-dimethylpyrrol-1-yl)-6-(4-(3-aminopropyl) phenyl)-pyridine,which was then converted as follows: To a 100 mL round-bottomed flaskequipped with N₂ inlet were added 300 mg (0.984 mmol) 2-(2,5-dimethylpyrrol-1-yl)-6-(4-(3-aminopropyl)phenyl)-pyridine, 156 uL(1.18 mmol) 1, 2, 3, 4-tetrahydronapthalen-2-one, 7 mL methanol, and 74mg (1.18 mmol) sodium cyanoborohydride, followed by 3 mL of 1 N HCI inmethanol. The reaction was stirred at room temperature for 6 h, pouredinto aqueous sodium bicarbonate solution, and extracted into ethylacetate. The organic layer was washed with water and brine, dried oversodium sulfate, and evaporated. The residue was chromatographed onsilica gel using methanol/methylene chloride as eluant to afford 2-(2,5-dimethylpyrrolyl)-6-{4-[3-(1, 2, 3,4-tetrahydro-naphthalen-2-ylamino)-propyl]-phenyl}-pyridine as an oil,120 mg (28%).

[0914]¹H-NMR (CDCl₃, δ): 1.70 (m, 1H), 1.99 (m, 2H), 2.11 (m, 1H), 2.205(s, 6H), 2.7-2.9 (m, 6H), 3.04 (m, 3H), 3.6 (bs, 1H), 5.92 (s, 2H),7.0-7.2 (m, 5H), 7.27 (m, 2H), 7.69 (d, J=8, 1H), 7.84 (t, J=8, 1H),7.96 (m, 2H).

[0915]¹³C-NMR (CDCl₃, δ): 13.5, 27.9, 28.4, 30.5, 33.2, 45.9, 54.0,106.9, 118.1, 119.6, 125.8, 126.0, 127.0, 128.6, 128.8,129.3,. 134.2,138.6, 142.9, 151.6, 156.8.

[0916] MS (%): 436 (parent+1, 100).

[0917] The oil was taken up 5 mL ethanol and 1 mL water and treated with96 mg (1.38 mmol, 5 eq.) hydroxylamine hydrochloride at 80° C. for 36 h.The reaction was cooled, poured into dilute aqueous hydrochloric acid,and washed with ethyl acetate. The pH of the aqueous layer was adjustedto 10 with 1 N sodium hydroxide solution followed by extraction withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and evaporated to afford an oil, 65 mg (66%), which wasconverted to the hydrochloride salt using HCl in ether, mp 120-130° C.

[0918]¹H-NMR (CDCl₃, δ): 1.57 (m, 2H), 1.87 (m, 2H), 2.6-3.0 (m, 9H),4.58 (bs, 2H), 6.40 (d, J=8, 1H), 7.0-7.1 (m, 5H), 7.25 (m, 2H), 7.469t, J=8, 1H), 7.83 (m, 2H).

[0919]³C-NMR (CDCl₃, δ): 28.1, 29.6, 31.9, 33.5, 36.8, 46.6, 53.6,106.9, 110.7, 125.7, 125.8, 126.8, 128.6, 128.7, 129.4, 135.3, 136.3,137.4, 138.4, 142.6, 156.1,158.3.

[0920] MS (%): 358 (parent+1, 100).

[0921] Anal. Calc'd. for C₂₄H₂₇N₃2HCl⅔H₂O: C 65.15, H 6.91, N 9.50.Found: C 65.01, H 7.10, N 9.22.

EXAMPLE 1286-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-4-methyl-pyridin-2-ylamine:refer to Scheme 3

[0922] A. ((4-Iodophenyl)acetyl)-phenethylpiperazine: To a 100 mLround-bottomed flask equipped with N₂ inlet were added 1.0 g (3.816mmol) 4-iodophenylacetic acid, 725 mg (3.816 mmol) phenethylpiperazine,10 mL dry acetonitrile, 10 mg 1-hydroxybenzotriazole, 732 mg (3.816mmol) EDAC, and 1.17 mL (8.395 mmol) triethylamine. The reaction wasstirred at room temperature for 16 hr, evaporated, and chromatographedon silica gel using methanol/methylene chloride as eluant to afford 1.74g (100%) of a low-melting solid.

[0923]¹H-NMR (CDCl₃, δ): 2.34 (m, 2H), 2.45 (m, 2H), 2.58 (m, 2H), 2.75(m, 2H), 3.43 (m, 2H), 3.63 (s, 2H), 3.65 (m, 2H), 6.97 (m, 2H), 7.17(m, 3H), 7.25 (m, 2H), 7.62 (m, 2H).

[0924]¹³C-NMR (CDCl₃, δ): 33.5, 40.2, 41.8, 46.0, 52.7, 53.2, 60.1,92.2, 126.1, 128.4, 128.5, 128.7, 130.8, 134.8, 137.7, 139.95, 168.7.

[0925] MS (%): 435 (parent+1, 100).

[0926] B. ((4-Iodophenyl)ethyl)-phenethylpiperazine: To a 100 mLround-bottomed flask equipped with condenser and N2 inlet were added1.66 g (3.8 mmol) ((4-iodophenyl)acetyl)-phenethylpiperazine, 15 mL drytetrahydrofuran, and 5.73 mL (11.46 mmol) of a 2.0 M solution of boranemethyl sulfide in tetrahydrofuran. The reaction was refluxed 18 hr,cooled, and evaporated. The residue was taken up in 25 mL ethanol, andtreated with 1 g sodium carbonate and 1 g cesium fluoride, then refluxed18 hr. The reaction was cooled, evaporated, and the residue taken up inwater/ethyl acetate. The organic layer was separated, washed with waterand brine, dried over sodium sulfate, and evaporated. The resultingsolid, mp 91-93° C. (0.74 g, 46%) was used directly.

[0927]¹H-NMR (CDCl₃, δ): 2.5-2.7 (m, 12H), 2.71 (m, 2H), 2.77 (m, 2H),6.94 (m, 2H), 7.19 (m, 3H), 7.26 (m, 2H), 7.58 (m, 2H).

[0928]³C-NMR (CDCl₃, δ): 33.1, 33.6, 53.2, 60.2, 60.6, 91.1, 126.0,128.4, 128.7, 130.8, 137.4, 140.0, 140.3.

[0929] MS (%): 420 (parent+1, 100).

[0930] C. 2-(2, 5-Dimethylpyrrolyl)-4-methylpyridine: To a 250 mLround-bottomed flask equipped with condenser were added 10.8 g (100mmol) 2-aminopyridine, 11.7 mL (100 mmol) hexane-2, 5-dione, and 0.5 mLconcentrated hydrochloric acid. The reaction was heated slowly to 150°C. over 2 hr, then at 165-170° C. for 2 hr, and cooled. The residue waspoured into aqueous sodium bicarbonate solution, extracted into ethylacetate, and the organic layer washed with water and brine, dried oversodium sulfate, and evaporated. The residue was chromatographed onsilica gel using ethyl acetate in hexane as eluant to afford alow-melting solid, 15.36 g (83%).

[0931]¹H-NMR (CDCl₃, δ): 2.11 (s, 6H), 2.41 (s, 3H), 5.87 (s, 2H), 7.02(bs, 1 H), 7.10 (m, 1H), 8.44 (d, J=5, 1H).

[0932]¹³C-NMR (CDCl₃, δ): 13.1, 21.0, 106.7, 122.75, 123.4, 128.5,149.0, 149.4, 152.2.

[0933] MS (%): 187 (parent+1, 100).

[0934] D. 2-(2, 5-Dimethylpyrrol-1-yl)-4-methyl-6-(4-(2-(phenethylpiperazin-4-yl)ethyl)phenyl)-pyridine:To a 100 mL three-necked round-bottomed flask equipped with septum andN₂ inlet were added 440 mg (1.05 mmol) of((4-iodophenyl)ethyl)-phenethylpiperazine and 5 mL dry ether. Thesolution was cooled to −70° C., and 0.625 mL of a 1.6 M solution (1.0mmol) of butyl lithium in hexanes added dropwise over 5 min. Thereaction was stirred 5 min at −70° C., then warmed to room temperature,and a solution of 186 mg (1.0 mmol) 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-pyridine in 5 mL dry ether added over 3min. The reaction turned to dark orange and then dark red as it wasstirred at room temperature for 5 hr, then quenched with aqueousammonium chloride. The organic layer was diluted with ethyl acetate andseparated, washed with aqueous ammonium chloride and brine, dried oversodium sulfate for 14 hr in the air (to permit air oxidation to thepyridine) and evaporated. The residue was chromatographed on silica gelusing aqueous acetonitrile as eluant to afford the product as an oil,165 mg (34.5%).

[0935]¹H-NMR (CDCl₃, δ): 2.19 (s, 6H), 2.45 (s, 3H), 2.6-2.9 (m, 16H),5.90 (s, 2H), 6.93 (m, 2H), 7.20 (m, 3H), 7.27 (m, 3H), 7.57 (m, 2H),7.96 (d, J=8, 1H).

[0936]¹³C-NMR (CDCl₃, δ): 13.5, 21.3, 33.0, 33.5, 53.0, 60.0, 60.4,106.7, 119.2, 120.5, 126.1, 127.0, 128.4, 128.6, 128.7, 129.1, 130.8,137.4, 139.8, 140.1, 151.8, 156.5.

[0937] MS (%): 479 (parent+1, 100).

[0938] E.6-(4-(2-(Phenethylpiperazin-4-yl)ethyl)phenyl)-4-methyl-pyridinyl-2-amine:To a 100 mL three-necked round-bottomed flask equipped with septum andN₂ inlet were added 165 mg (0.345 mmol) 2-(2,5-dimethylpyrrol-1-yl)-4-methyl-6-(4-(2-(phenethylpiperazin-4-yl)ethyl)phenyl)-pyridine,120 mg (1.726 mmol) hydroxylamine hydrochloride, 1 mL water, and 5 mLethanol. The reaction was refluxed 14 hr, cooled, evaporated, and takenup in ethyl acetate. The organic layer was washed with water and brine,dried over sodium sulfate, and evaporated. The residue waschromatographed on silica gel using methanol/methylene chloride aseluant to afford an oil, which was converted to the hydrochloride saltusing 1 N HCl in ether to give 18 mg (10%), mp 242-250° C.

[0939]¹H-NMR (CDCl₃, δ): 2.22 (s, 3H), 2.63 (m, 4H), 2.79 (m, 12H), 6.24(s, 1H), 6.80 (s, 1H), 7.1-7.3 (m, 7H), 7.71 (m, 2H).

[0940]¹³C-NMR (CDCl₃, δ): 21.1, 32.8, 33.0, 52.6, 59.9, 60.1, 107.7,112.6, 126.2, 127.0, 128.4, 128.6, 128.8, 139.5, 140.2, 149.8, 158.4.

[0941] MS (%): 401 (parent+1, 100).

EXAMPLE 1296-{4-[3-(4-Phenethyl-piperazin-1-yl)-propyl]-phenyl}-pyridin-2-ylamine

[0942] Prepared as in Example 128, starting from3-(4-bromophenyl)-propionic acid, prepared in Example 125, concludingwith deblocking with hydroxylamine hydrochloride, affording a residuewhich was purified by column chromatography using methanol/methylenechloride to give a 46% yield of an oil, which was converted to thehydrochloride salt using 1 N HCl in ether to give mp 125-140° C.

[0943]¹H-NMR (CDCl₃, δ): 1.87 (m, 2H), 2.4) (m, 4H), 2.5-2.7 (m, 10H),2.81 (m, 2H), 4.73 (bs, 2H), 6.38 (d, J=8, 1H), 7.01 (d, J=7.5, 1H),7.1-7.3 (m, 7H), 7.44 (t, J=8, 1H), 7.80 (m, 2H).

[0944]¹³C-NMR (CDCl₃, δ): 28.3, 32.7,. 33.5, 53.0, 57.95, 60.5, 107.0,110.7, 126.0, 126.9, 128.4, 128.6, 137.3, 138.0, 138.4, 140.3, 142.6,156.2, 158.4.

[0945] MS (%): 401 (parent+1, 100).

[0946] Anal. Calc'd. for C₂₆H₃₂N₄3HClH₂O: C 59.15, H 7.06, N 10.61.Found: C 58.67, H 7.02, N 11.23.

EXAMPLE 1306-{3-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0947] Prepared using the procedures in Example 1, with 3-aminophenethylalcohol as starting material, with the final condensation stepproceeding in 25% yield after chromatography on silica gel usingmethanol/methylene chloride as eluant. The product was precipitated fromether as the hydrochloride salt using 1 N HCl in ether, mp 120° C.(dec.).

[0948]¹H-NMR (δ, CDCl₃): 2.5-2.7 (m, 12H), 2.80 (m, 2H), 2.87 (m, 2H),4.54 (bs, 2H), 6.41 (d, J=8, 1H), 7.05 (d, J=7, 1H), 7.20 (m, 4H), 7.25(m, 2H), 7.33 (t, J=8, 1H), 7.46 (t, J=8, 1H), 7.73 (m, 1H), 7.78 (s,1H).

[0949]¹³C-NMR (δ, CDCl₃): 33.6, 33.7, 53.2, 60.5, 60.6, 107.1, 111.0,124.6, 126.0, 127.2, 128.4, 128.6, 128.7, 129.0, 138.3, 139.8, 140.3,140.6, 156.2, 158.3.

[0950] MS (%): 387 (parent+1, 100).

[0951] Anal. Calc'd. for C₂₅H₃₀N₄2HCl½CH₂Cl₂H₂O: C 58.91, H 6.19, N10.78. Found: C 59.22, H 6.64, N 10.38.

EXAMPLE 131 6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine cisdiastereomer)

[0952] Prepared as in Example 108, using the trans isomer of N-benzyl-2,6-dimethylpiperidin-4-one from Example 108A, with the final step in 92%yield, as the hydrochloride salt.

[0953]¹H-NMR (CDCl₃, δ): 1.05 (m, 6H), 1.47 (m, 2H), 1.71 (m, 2H), 2.54(m, 2H), 2.71 (m, 2H), 2.83 (m, 2H), 3.34 (m, 1H), 4.49 (bs, 2H), 6.41(d, J=8, 1H), 7.05 d, J=8, 1H), 7.25 (m, 2H), 7.46 (t, J=8, 1H), 7.82(m, 2H).

[0954]¹³C-NMR (CDCl₃, δ): 11.3, 21.4, 35.6, 41.4, 44.1, 45.5, 48.8,51.1, 51.2, 106.8, 110.7, 126.7, 128.9, 137.5, 138.3, 141.5, 156.1,158.2.

[0955] FAB MS (%): 325 (parent+1, 4), 279 (20), 167 (45), 149 (100), 113(36).

[0956] HRMS Calc'd. for C₂₀H₂₉N₄ (parent+1): 325.2392. Found: 325.2369.

EXAMPLE 132 6-{4-[2-(4-Amino-2,6-diisopropyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine (cisdiastereomer)

[0957] Prepared as in Example 108 using isopropanal, to afford theproduct as an oil in 90% yield in the final step, which was converted tothe hydrochloride salt as an amorphous solid.

[0958]¹H-NMR (CDCl₃, δ): 0.8-1.0 (m, 12H), 1.60 (m, 4H), 1.84 (m, 2H),2.13 (m, 1H), 2.37 (m, 1H), 2.51 (m, 1H), 2.65 (m, 2H), 2.76 (m, 2H),4.54 (bs, 2H), 6.39 (d, J=8, 1H), 7.03 (d, J=8, 1H), 7.21 (m, 2H), 7.44(t, J=8, 1H), 7.81 (m, 2H).

[0959]³C-NMR (CDCl₃, δ): 20.6, 20.8, 21.1, 27.1, 29.6, 29.9, 33.9, 36.6,46.2, 47.8, 60.4, 63.0, 106.7, 110.6, 126.6, 128.9, 137.2, 138.2, 141.5,156.0, 158.2.

[0960] APCI MS (%): 381 (parent+1, 100).

EXAMPLE 1336-{4-[2-(4-Isobutyl-piperazin-1-yl)-1-methyl-ethyl]-phenyl}-pyridin-2-ylamine

[0961] A. 2-(2,5-Dimethylpyrrolyl)-6-((4-(1-cyanoethyl)phenyl))-pyridine: To a 100 mLround-bottomed flask equipped with septum and N₂ inlet were added 500 mg(1.74 mmol) 2-(2,5-dimethylpyrrolyl)-6-(4-(cyanomethyl)phenyl))-pyridine (Example 112)and 17 mL dry tetrahydrofuran. The solution was cooled to −78° C., and1.92 mL (1.92 mmol) of a 1.0 M solution of lithiumbistrimethylsilylamide was added dropwise over 3 minutes. After stirringfor 15 minutes, 0.23 mL (3.66 mmol) methyl iodide was added, andstirring continued at −78° C. for another 15 minutes. The reaction wasthen poured into aqueous ammonium chloride and extracted into ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate, and evaporated. The residue was chromatographed on silica gelwith hexane/ethyl acetate as eluant to afford 404 mg (77%) of an oil.

[0962]¹H-NMR (CDCl₃, δ): 1.67 (d, J=7, 3H), 2.22 (s, 6H), 3.96 (q, J=7,1H), 5.95 (s, 2H), 7.17 (d, J=8, 1H), 7.45 (m, 2H), 7.75 (d, J=8, 1H),7.89 (t, J=8, 1H), 8.10 (m, 2H).

[0963]¹³C-NMR (CDCl₃, δ): 13.5, 21.4, 31.1, 107.1, 118.3, 120.2, 121.4,127.2, 127.7, 128.7, 138.2, 138.3, 138.8, 141.8, 156.0.

[0964] IR (neat, KBr): 2240 (CN).

[0965] FAB MS (%): 302 (parent+1, 4), 279 (20), 167 (45), 149 (100), 113(36).

[0966] B. 2-(2,5-Dimethylpyrrolyl)-6-((4-(1-carboxyethyl)phenyl))-pyridine: To a 100 mLround-bottomed flask equipped with condenser and N₂ inlet were added 400mg (1.33 mmol) 2-(2,5-dimethylpyrrolyl)-6-((4-(1-cyanoethyl)phenyl))-pyridine and 20 mLethanol. After heating to reflux, 30 mL of a 10% aqueous solution ofsodium hydroxide was added dropwise slowly, and refluxing was continuedovernight. The reaction was cooled and the pH adjusted to 1 with 6 Nhydrochloric acid, then extracted into ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, and evaporated to abrown solid, mp 149-155° C., 384 mg (90.5%).

[0967]¹H-NMR (CDCl₃, δ): 1.55 (d, J=7, 3H), 2.22 (s, 6H), 3.80 (q, J=7,1H), 5.95 (s, 2H), 7.14 (d, J=8, 1H), 7.43 (m, 2H), 7.73 (d, J=8, 1H),7.87 (t, J=8, 1H), 8.05 (m, 2H).

[0968]³C-NMR (CDCl₃, δ): 13.5, 18.1, 45.2, 107.0, 118.3, 119.9, 127.3,128.1, 128.7, 137.5, 138.65, 141.1, 151.7, 156.5, 180.4.

[0969] FAB MS (%): 321 (parent+1, 4), 279 (20), 167 (45), 149 (100), 113(36).

[0970] Anal. Calc'd. for C₂₀H₂₀N₂O₂¼H₂O: C 73.94, H 6.36, N 8.62. Found:C 73.95, H 6.18, N 8.41.

[0971] C. 2-(2,5-Dimethylpyrrolyl)-6-((4-(1-(4-isobutylpiperazin-1-ylamido)ethyl)phenyl))-pyridine:To a 100 mL round-bottomed flask equipped with condenser and N₂ inletwere added 187 mg (0.584 mmol) 2-(2,5-dimethylpyrrolyl)-6-((4-(1-carboxyethyl)phenyl))-pyridine, 124 mg(0.584 mmol) N-isobutylpiperazine hydrochloride,112 mg (0.584mmol)N-ethyl-N-3-dimethylaminopropyl-carbodiimide, 79 mg (0.584 mmol) 1-hydroxybenztriazole, 0.2 mL (1.461 mmol) triethylamine, and 6 mLacetonitrile. The reaction was stirred at room temperature for 24 h,poured into aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was washed with brine, dried over sodium sulfate, andevaporated. The residue was chromatographed on silica gel usingmethanol/methylene chloride as eluant to afford 218 mg (84%) of an oil.

[0972]¹H-NMR (CDCl₃, δ): 0.82 (d, J=7, 6H), 1.45 (d, J=7, 3H), 1.68 (m,1H), 1.88 (m, 1H), 1.96 (m, 2H), 2.20 (s, 6H), 2.2 (m, 2H), 2.37 (m,1H), 3.33 (m,1H), 3.42 (m, 1H), 3.54 (m, 1H), 3.74 (m, 1H), 3.93 (q, J=7,1H), 5.92 (s, 2H), 7.12 d, J=8, 1H), 7.24 (m, 2H), 7.72 (d, J=8, 1H),7.85 (t, J =8, 1H), 8.01 (m, 2H).

[0973]¹³C-NMR (CDCl₃, δ): 13.5, 20.6, 20.7 25.3, 42.0, 43.0, 45.5, 53.1,53.3, 66.5, 107.0, 118.2, 119.8, 127.5, 127.7, 128.6, 136.9, 138.6,143.5, 151.7, 156.5, 171.7.

[0974] APCI MS (%): 445 (parent+1, 100).

[0975] D2-(2,5-Dimethylpyrrolyl)-6-{4-[2-(4-isobutyl-piperazin-1-yl)-1-methyl-ethyl]-phenyl}-pyridine:To a 100 mL round-bottomed flask equipped with condenser and N₂ inletwere added 218 mg (0.491 mmol) 2-(2,5-dimethylpyrrolyl)-6-((4-(l-(4-isobutylpiperazin-1-ylamido)ethyl)phenyl))-pyridine,20 mL dry tetrahydrofuran, and 10 mL (20 mmol) of a 2.0 M solution ofborane methyl sulfide in tetrahydrofuran.

[0976] The solution was refluxeo 24 hr, cooled, and the tetrahydrofuranevaporated. The residue was treated with 25 mL ethanol, 1 g sodiumcarbonate, and 300 mg cesium fluoride, and refluxed 24 hr. The reactionwas cooled, poured into 1 N hydrochloric acid, and washed with ethylacetate. The aqueous layer was adjusted to pH 10 with 6 N sodiumhydroxide solution and extracted into ethyl acetate. The organic layerwas washed with brine, dried over sodium sulfate, and evaporated. Bothorganic layers were collected, and the first one used subsequently.

[0977] APCI MS (%): 431 (parent+1, 1 00).

[0978] E.6-{4-[2-(4-Isobutyl-piperazin-1-yl)-1-methyl-ethyl]-phenyl}-pyridin-2-ylamine:

[0979] Prepared using hydroxylamine hydrochloride as in Example 124F.Purification was effected by making the N-trityl derivative usingtriphenylmethyl chloride and triethylamine in methylene chloride at roomtemperature overnight, followed by chromatography on silica gel usingmethanol/methylene chloride as eluant, and then removal of the tritylgroup using 50% aqueous formic acid at 55° C. for 1 h, followed byfiltration, adjustment of the filtrate to pH 10 with 6 N sodiumhydroxide solution, and extraction into ethyl acetate. The resultingmaterial was converted to the hydrochloride salt using HCl in ethylether to give a white solid, mp 250-260° C., in 17% yield.

[0980] H-NMR (CDCl₃, δ): 0.86 (d, J=7, 6H), 1.26 (d, J=6, 3H), 1.74 (m,J=7, 1H), 2.04 (d, J=7, 2H), 2.37 (m, 6H), 2.47 (d, J=7, 2H), 2.97 (m, 1H), 4.48 (bs, 2H), 6.40 (d, J=8, 1H), 7.03 (d, J=7.5, 1H), 7.25 (m, 2H),7.46 (t, J=8, 1H), 7.82 (m, 2H).

[0981]¹³C-NMR (CDCl₃, δ): 20.1, 20.9, 25.3, 37.2, 53.5, 66.0, 66.9,106.7, 110.7, 126.7, 127.3, 127.8, 137.5, 138.2, 146.9, 156.1, 158.1.

[0982] APCI MS (%): 353 (parent+1, 100.

[0983] Anal. Calc'd. for C₂₂H₃₂N₄3HCl{fraction (3/2)}H₂O½(C₄H₁₀O): C55.12, H 7.71, N 10.71. Found: C 55.47, H 8.10, N 10.52.

EXAMPLE 1346-{4-[1-Benzyl-2-(4-isobutyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[0984] Prepared as in Example 133 using benzyl bromide in the alkylationanalogous to Example 133A in 13% yield for the final deblocking step,converted to the hydrochloride salt in ether.

[0985]¹H-NMR (CDCl₃, δ): 0.86 (d, J=6, 6H), 1.73 (m, J=6, 1H), 2.03 (d,J=7, 2H), 2.37 (m, 6H), 2.53 (m, 3H), 2.69 (m, 1H), 2.83 (m, 1H), 3.14(m, 2H), 4.465 (bs, 2H), 6.40 (d, J=8, 1H), 6.97 (m, 2H), 7.03 (d,J=7.5, 1H), 7.13 (m, 5H), 7.45 (t, J=8, 1H), 7.78 (m, 2H).

[0986]¹³C-NMR (CDCl₃, δ): 20.9, 25.3, 40.6, 45.1, 53.4, 53.5, 63.7,66.8, 106.7, 110.7, 125.6, 126.5, 127.9, 128.1, 129.1, 137.4, 138.2,140.4, 144.5, 156.0, 158.1.

[0987] APCI MS (%): 429 (parent+1, 100).

[0988] Anal. Calc'd. for C₂₈H₃₆N₄ ³HClH₂O½(C₄H₁₀O): C 60.76, H 7.82, N9.45. Found: C 61.14, H 7.93, N 9.17.

EXAMPLE 135 6-[4-(Phenethylamino-methyl)-phenyl]-pyridin-2-ylamine

[0989] A. 2-(2, 5-Dimethylpyrrolyl)-6-(4-carboxyphenyl)-pyridine:Prepared as in Example 112A, using 4-carboxyphenyl boronic acid, in 22%yield, as a low-melting solid.

[0990]¹H-NMR (CDCl₃, δ): 2.22 (s, 6H), 5.94 (s, 2H), 7.21 (d, J=8, 1H),7.81 (d, J=8, 1H), 7.92 (t, J=8, 1H), 8.18 (m, 4H).

[0991] APCI MS (%): 293 (parent+1, 100).

[0992] B. 2-(2,5-Dimethylpyrrolyl)-6-(4-(N-phenethylcarboxamido)-phenyl)-pyridine:Prepared as in Example 108F, using the above and phenethylamine, in 70%yield, as a low-melting yellow solid.

[0993]¹H-NMR (CDCl₃, δ): 2.20 (s, 6H), 2.95 (t, J=7, 2H), 3.73 (dt,J=5,7, 2H), 5.925 (s, 2H), 6.17 (broad triplet, J=5, 1H), 7.17 (d, J=8,1H), 7.24 (m, 3H), 7.31 (m, 2H), 7.78 (m, 3H), 7.89 (t, J=8, 1H), 8.10(m, 2H).

[0994] APCI MS (%): 396 (parent+1, 100).

[0995] C. 6-(4-(N-phenethylcarboxamido)phenyl)-pyridin-2-ylamine:Prepared as in Example 1F, in 36% yield, as a low-melting tan solid.

[0996]¹H-NMR (CDCl₃, δ): 2.94 (t, J=7, 2H), 3.72 (dt, J=5, 7, 2H), 4.93(bs, 2H), 6.175 (m, 1H), 6.52 (d, J=8, 1H), 7.09 (d, J=7, 1H), 7.24 (m,3H), 7.31 (m, 2H), 7.54 (t, J=8, 1H), 7.75 (m, 2H), 7.97 (m, 2H).

[0997] APCI MS (%): 318 (parent+1, 100).

[0998] D. 6-[4-(Phenethylamino-methyl)-phenyl]-pyridin-2-ylamine:Prepared as in Example 133D in 61% yieid, mp 236-238° C., as thehydrochloride salt.

[0999]¹H-NMR (CDCl₃, δ): 2.81-2.85 (m, 2H), 2.88-2.92 (m, 2H), 3.84 (s,2H), 4.47 (bs, 2H), 6.43 (d, J=8, 1H), 7.05 (d, J=8, 1H), 7.18-7.29 (m,3H), 7.24-7.27 (m, 2H), 7.29-7.34 (m, 2H), 7.47 (t, J=8, 1H), 7.86 (d,J=8, 1H).

[1000]¹³C-NMR (CDCl₃, δ) 33.3, 49.4, 50.0, 51.7, 112.3, 113.4, 128.3,129.1, 129.8, 130.0, 132.3, 136.1, 137.8, 145.8, 147.2, 157.4.

[1001] MS (%): 304 (parent+1, 100).

EXAMPLE 1366-{4-[(Cyclohexyl-methyl-amino)-methyl]-phenyl}-pyridin-2-ylamine

[1002] Prepared as in Example 135 in 43% yield, mp>250° C., as thehydrochloride salt.

[1003]¹H-NMR (CDCl₃, δ): 1.10-1.30 (m, 5H), 1.60-1.63 (m, 1H), 1.63-1.87(m, 4H), 2.20 (s, 3H), 2.41-2.46 (m, 1H), 3.60 (bs, 2H), 4.48 (bs, 2H),6.44 (d, J=8, 1H), 7.06 (d, J=8, 1H), 7.41-7.50 (m, 3H), 7.83-7.87 (m,2H).

[1004] MS (%): 296 (parent+1, 100).

EXAMPLE 1376-[4-(4-Amino-piperidin-1-ylmethyl)-phenyl}-pyridin-2-ylamine

[1005] Prepared as in Example 135 as an amorphous solid in 25% yield.

[1006]¹H-NMR (CDCl₃, δ): 1.30-1.34 (m, 2H), 1.71-1.74 (m, 2H), 1.97-2.00(m, 2H), 2.57-2.60 (m, 1H), 2.77-2.80 (m, 2H), 3.46 (s, 2H), 6.39 (d,J=8, 1H), 6.94 (d, J=8, 1H), 7.27-7.29 (m, 2H), 7.42 (t, J=8, 1H),7.70-7.73 (m, 2H).

[1007] MS (%): 283 (parent+1, 100).

EXAMPLE 138 6-(4-Piperidin-1-ylmethyl-phenyl)-pyridin-2-ylamine

[1008] Prepared as in Example 135 in 53% yield, mp>250° C., as thehydrochloride salt.

[1009]¹H-NMR (CDCl₃, δ): 1.40-1.42 (m, 2H), 1.54-1.59 (m, 4H), 2.39 (bs,4H), 3.51 (s, 2H), 4.50 (bs, 2H), 6.42 (d, J=8, 1H), 7.05 (d, J=8, 1H),7.36 (d, J=8, 2H), 7.47 (t, J=8, 1H), 7.84 (d, J=8, 2H).

[1010]¹³C-NMR (CDCl₃, δ): 24.2, 25.7, 54.3, 63.4, 106.9, 110.8, 126.5,129.5, 138.3, 156.0.

[1011] MS (%): 268 (parent+1, 100).

EXAMPLE 139 6-[4-(Indan-2-ylaminomethyl)-phenyl]-pyridin-2-ylamine

[1012] Prepared as in Example 135 in 35% yield, mp 185-187° C., as thehydrochloride salt.

[1013]¹H-NMR (CDCl₃, δ): 2.81 (dd, J₁=9, J₂=6, 2H), 3.16 (dd, J₁=9,J₂=6, 2H), 3.66-3.69 (m, 1H), 3.89 (s, 2H), 4.48 (bs, 2H), 6.42 (d, J=8,1H), 7.06 (d, J=8, 1H), 7.11-7.20 (m, 2H), 7.40 (d, J=8, 1H), 7.49 (t,J=7, 1H), 7.88 (d, J=8, 1H).

[1014]¹³C-NMR (CDCl3, δ): 39.8, 51.9, 58.8, 107.0, 110.9, 124.7, 126.4,126.9, 128.5, 138.4.

[1015] MS (%): 316 (parent+1, 100).

EXAMPLE 140 6-{4- [(2-Thiorpen-2-yl-ethylamino)-methyl]-phenyl}pyridin-2-ylamine

[1016] Prepared as in Example 135 in 68% yield as an amorphous solid

[1017]¹H-NMR (CDCl₃, δ): 2.92 (t, J=6, 2H), 3.04 (t, J=6, 2H), 3.84 (s,2H), 4.48 (bs, 2H), 6.43 (d, J=8, 1H), 6.81-6.82 (m, 1H), 6.91-6.93(m,1H), 7.06 (d, J=8, 1H), 7.13 (m, 1H), 7.34 (d, J=8, 2H), 7.48 (t,J=7, 1H), 7.86 (d, J=8, 2H).

[1018]¹³C-NMR (CDCl₃, δ): 30.4, 50.3, 53.3, 106.9, 110.8, 123.5, 124.9,126.8, 128.2, 138.3, 140.6, 142.9, 155.7, 158.2.

[1019] MS (%): 310 (parent+1, 100).

EXAMPLE 1416-[2-Methoxy-4-(phenethylamino-methyl)-phenyl]-pyridin-2-ylamine Referto Scheme 5

[1020] A. 2-Methoxy-4-methylphenylboronic acid: To a 125 mL three-neckedround-bottomed flask equipped with septum and N₂ inlet were added 2.3 g(11.4 mmol) 2-bromo-5-methylanisole (prepared as described in EP 470794A1, see Chem. Abs., 116:193935) and 25 mL dry tetrahydrofuran. Thesolution was cooled to −70° C., and 5.5 mL (13.7 mmol) of a 2.5 Msolution of butyl lithium in hexane added over 3 min. The reaction wasstirred 1 h at −70° C., then 2.34 mL (13.7 mmol) triethyl borate wasadded, and stirring continued for 2 h at −70° C. The reaction was warmedto room temperature and stirred for 60 h, quenched with aqueous ammoniumchloride solution and dilute hydrochloric acid solution, and extractedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate and evaporated to a dark oil, which was triturated withhexane to afford 630 mg (33%) of an oil.

[1021]¹H-NMR (CDCl₃, δ): 2.37 (s, 3H), 3.89 (s, 3H), 6.715 (s, 1H), 6.84(d, J=7, 1H), 7.70 (d, J=7, 1H).

[1022] B. 2-(2,5-Dimethylpyrrolyl)-6-(2-methoxy-4-methylphenyl)-pyridine: Prepared asin Example 112A, using 953 mg (3.795 mmol) 2-(2,5-dimethyl)-6-bromopyridine, 630 mg (3.795 mmol)2-methoxy-4-methylphenylboronic acid, 1.61 g (15.18 mmol) sodiumcarbonate, 44 mg (0.038 mmol) tetrakis-triphenylphosphine palladium, 18mL ethanol, and 2 mL water, to give 670 mg (60%) of an oil.

[1023]¹H-NMR (CDCl₃, δ): 2.28 (s, 6H), 2.45 (s, 3H), 3.93 (s, 3H), 5.98(s, 2H), 6.87 (s, 1H), 6.94 (d, J=8, 1H), 7.14 (d, J=8, 1H), 7.84 (t,J=8, 1H), 7.91 (d, J=8, 1H), 7.98 (d, J =8, 1H).

[1024]¹³C-NMR (CDCl₃, δ): 13.4, 21.7, 55.4, 106.7, 112.2, 119.2, 121.8,123.1, 125.1, 128.6, 131.2, 137.6, 140.6, 151.3, 155.6, 157.1.

[1025] APCI MS (%): 293 (parent+1, 100).

[1026] C. 6-(2-Methoxy-4-methylphenyl)-pyridin-2-ylamine: Prepared as inExample 1F in 90% yield, as an oil.

[1027]¹H-NMR (CDCl₃, δ): 2.365 (s, 3H), 3.785 (s, 3H), 4.67 (bs, 2H),6.34 (d, J=8, 1H), 6.76 (s, 1H), 6.84 (d, J=8, 1H), 7.09 (d, J=7.5, 1H),7.39 (t, J=8, 1H), 7.57 (d, J=8, 1H).

[1028]¹³C-NMR (CDCl₃, δ): 21.6, 55.4, 106.5, 112.15, 114.95, 121.5,126.5, 130.6, 137.4, 139.5, 154.3, 156.7, 158.2.

[1029] APCI MS (%): 215 (parent+1, 100).

[1030] D. 2-Phthalimido-6-(2-methoxy-4-methylphenyl)-pyridine: To a 100mL round-bottomed flask equipped with condenser and N₂ inlet were added440 mg (2.15 mmol) 6-(2-methoxy-4-methylphenyl)-pyridin-2-ylamine, 502mg (2.29 mmol) N-carbethoxyphthalimide, and 20 mL dry toluene. Thesolution was refluxed 14 h, cooled, and purified by chromatography onsilica gel using hexane/ethyl acetate as eluant to afford 710 mg (90%)of a low-melting solid.

[1031]¹H-NMR (CDCl₃, δ): 2.355 (s, 3H), 3.84 (s, 3H), 6.775 (s, 1H),6.85 (d, J=8, 1H), 7.27 (m, 1H), 7.76 (m, 3H), 7.83 (t, J=8, 1H), 7.92(m, 3H).

[1032]¹³C-NMR (CDCl₃, δ): 21.3, 55.2, 112.0, 119.6, 121.6, 123.5, 124.7,131.0, 131.5, 133.9, 134.4, 135.3, 137.8, 140.6, 156.0, 156.8, 166.8.

[1033] APCI MS (%): 345 (parent+1, 100).

[1034] E. 2-Phthalimido-6-(2-methoxy-4-bromomethylphenyl)-pyridine: To a100 mL round-bottomed flask equipped with condenser and N₂ inlet wereadded 0.7 g (2.03 mmol)2-phthalimido-6-(2-methoxy-4-methylphenyl)-pyridine, 0.36 g (2.03 mmol)N-bromosuccinimide, 10 mg azobisisobutyronitrile, and 30 mL carbontetrachloride. The reaction was heated at 50° C. for 24 h, cooled,diluted with methylene chloride, and washed with aqueous sodiumbicarbonate solution, dried over magnesium sulfate, and evaporated. Thecrude residue, 0.81 g, was used directly.

[1035] APCI MS (%): 423/425 (parent+1, 100).

[1036] F.2-Phthalimido-6-[2-methoxy-4-(phenethylamino-methyl]phenyl)-pyridine: Toa 100 mL round-bottomed flask equipped with condenser and N₂ inlet wereadded 120 mg (0.28 mmol)2-phthalimido-6-(2-methoxy-4-bromomethylphenyl)-pyridine, 0.04 mL (0.3mmol) phenethylamine, 29 mg (0.35 mmol) sodium bicarbonate, and 6 mLacetonitrile. The reaction was heated at 50° C. for 8 h, cooled, andextracted into ethyl acetate. The organic layer was washed with brine,dried over magnesium sulfate, and evaporated. The residue waschromatographed on silica gel using methanol/methylene chloride toafford 40 mg (31 %) of an oil.

[1037]¹H-NMR (CDCl₃, δ): 2.85 (m, 2H), 2.89 (m, 2H), 3.84 (s, 2H), 3.85(s, 3H), 6.96 (m, 2H), 7.2-7.4 (m, 7H), 7.8-8.0 (m, 6H).

[1038] APCI MS (%): 464 (parent+1, 100).

[1039] G.6-[2-Methoxy-4-(phenethylamino-methyl)-phenyl]-pyridin-2-ylamine: To a100 mL round-bottomed flask equipped with condenser and N₂ inlet wereadded 30 mg (0.065 mmol)2-phthalimido-6-[2-methoxy-4-(phenethylamino-methyl]phenyl)-pyridine, 7uL (0.2 mmol) hydrazine, and 3 mL methanol. The reaction was heated at50° C. for 3.5 h, cooled, and concentrated. The residue was dissolved inmethylene chloride, washed with aqueous sodium bicarbonate solution,dried over magnesium sulfate, and evaporated. The res;,ue waschromatographed on silica gel using methanol/methylene chloride aseluant to afford 10 mg (46%) of an oil, which was converted to thehydrochloride salt.

[1040]¹H-NMR (CDCl₃, δ): 2.88-2.95 (m, 4H), 3.82 (s, 3H), 3.87 (s, 2H),6.43 (d, J=8, 1H), 6.94 (bs, 1H), 7.10 (d,J=8, 1H), 7.18-7.20 (m, 3H),7.25-7.29 (m, 2H), 7.45 (t, J=8, 1H), 7.61 (d, J=8, 1H).

[1041] MS(%): 334 (parent+1, 100).

EXAMPLE 1426-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-methoxy-phenyl}-pyridin-2-ylamine

[1042] Prepared as in Example 141, using N-methyl-cyclohexylamine, withan 86% yield in the final step.

[1043]¹H-NMR (CDCl₃, δ): 1.07-1.34 (m, 5H), 1.60-1.63 (m, 1H), 1.77-1.87(m, 4H), 2.22 (s, 3H), 2.42-2.47 (m, 1H), 3.59 (s, 2H), 3.83 (s, 3H),4.44 (bs, 2H), 6.41 (d, J=8, 1H), 7.95-7.98 (m, 2H), 7.13 (d, J=8, 1H),7.44 (t, J=8, 1H), 7.59 (d, J=8, 1H).

[1044]¹³C- NMR (CDCl₃, δ): 26.0, 26.5, 28.6, 37.8, 55.7, 57.9, 62.0,106.6, 111.6, 115.4, 121.3, 130.5, 137.5, 152.5, 157.0, 159.0.

[1045] MS (%) 326 (parent+1, 100).

EXAMPLE 1436-{4-[1-Cinnamyl-2-(4-isobutyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[1046] Prepared as in Example 133 using cinnamyl bromide in thealkylation analogous to Example 133A, in 98% yield for the finaldeblocking step, converted to the hydrochloride salt in ether.

[1047]¹H-NMR (CDCl₃, δ): 0.85 (d, J=7, 6H), 1.73 (m, J=6, 1H), 2.03 (d,J=7, 2H), 2.36 (m, 6H), 2.49 (m, 5H), 2.67 (m, 2H), 2.97 (m, 1H), 4.50(bs, 2H), 6.08 (m, 1H), 6.30 (m, 1H), 6.39 (d, J=8, 1H), 7.04 (d, J=7,1H), 7.12 (m, 1H), 7.21 (m, 7H), 7.45 (t, J =8, 1H), 7.82 (m, 2H).

[1048]¹³C-NMR (CDCl₃, δ): 21.0, 25.3, 38.1, 43.7, 53.6, 64.1, 66.9,106.9, 110.8, 126.0, 126.8, 128.1, 128.4, 128.8, 131.2, 137.7, 138.3,144.8, 156.1, 158.2.

[1049] APCI MS (%): 455 (parent+1, 100).

EXAMPLE 1446-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl}-pyridin-2-ylamine

[1050] A. 2-Fluoro-4-methylphenylboronic acid: Prepared as in Example141A, using 2-fluoro-4-methylbromobenzene, in 97% yield, as alow-melting solid.

[1051]¹H-NMR (CDCl₃, δ): 2.37 (s, 3H), 6.86 (d, J=8, 1H), 7.00 (d, J=8,1H), 7.685 (m, 1H).

[1052] B. 2-(2,5-Dimethylpyrrolyl)-6-(2-fluoro-4-methylphenyl)-pyridine: Prepared as inExample 141B, in 73% yield as a low-melting, yellow solid.

[1053]¹H-NMR (CDCl₃, δ): 2.20 (s, 6H), 2.37 (s, 3H), 5.91 (s, 2H), 6.97(d, J=8, 1H), 7.04 (d, J=8, 1H), 7.13 (d, J=7, 1H), 7.84 (m, 2H), 7.98(t, J=8, 1H).

[1054] APCI MS (%): 281 (parent+1, 100).

[1055] C. 6-(2-Fluoro-4-methylphenyl)-pyridin-2-ylamine: Prepared as inExample 141C in 68% yield, as an oil.

[1056]¹H-NMR (CDCl₃, δ): 2.35 (s, 3H), 6.43 (d, J=8, 1H), 6.92 (d, J=8,1H), 7.01 (m, 1H), 7.09 (m, 1H), 7.46 (t, J=8, 1H), 7.76 (t, J=8, 1H).

[1057] APCI MS (%): 203 (parent+1, 100).

[1058] D.2-Phthalimido-6-(2-fluoro-4-methyphenyl)-pyridine: Prepared asin Example 141D in 73% yield as a low-melting solid.

[1059]¹H-NMR (CDCl₃, δ): 2.37 (s, 3H), 6.96 (d, J=8, 1H), 7.04 (m, 1H),7.35 (dd, J =1, 8, 1H), 7.8-8.0 (m, 7H).

[1060] APCI MS (%): 333 (parent+1, 100).

[1061] E. 2-Phthalimido-6-(2-fluoro-4-bromomethylphenyl)-pyridine:Prepared as in Example 141E in 62% yield as a crude solid, which wasused directly in the following step.

[1062] APCI MS (%): 411/413 (parent +1, 45/42), remianing peaks due toimpurities.

[1063] F.2-Phthalimido-6-[2-fluoro-4-(N-cyclohexyl-N-methylamino-methyl]phenyl)-pyridine:Prepared as in Example 141F in 8% yield as an oil.

[1064]¹H-NMR (CDCl₃, δ): 1.22 (m, 6H), 1.6-1.8 (m, 4H), 2.22 (s, 3H),2.45 (m, 1H), 3.62 (s, 2H), 7.19 (d, J=7, 1H), 7.35 (dd, J=1,8, 1H),7.8-8.0 (m, 8H).

[1065] APCI MS (%): 444 (parent+1, 100).

[1066] G.6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl}-pyridin-2-ylamine:Prepared as in Example 141G in 57% yield as an oil, which was convertedto the hydrochloride salt.

[1067]¹H-NMR (hydrochloride salt in CD₃OD, δ): 1.16-1.48 (m, 7H),1.57-1.77 (m, 3H), 1.89-2.05 (m, 2H), 2.09-2.22 (m, 2H), 2.76 (s, 2H),7.05 (d, J=8, 1H), 7.16 (s, J=8, 1H), 7.58-7.66 (m, 2H), 7.83 (t, J=8,1H), 7.99 (t, J=8, 1H).

[1068] APCI MS(%): 314 (parent+1, 100).

EXAMPLE 1456-[4-((N-Phenethyl-N-methyl)amino-methyl)-phenyl]-pyridin-2-ylamine

[1069] Prepared as in Example 133D in 57% yield, mp>250° C., as thehydrochloride salt.

[1070]¹H-NMR (CDCl₃, δ): 2.30 (s, 3H), 2.67 (m, 2H), 2.83 (m, 2H), 3.60(s, 2H), 4.51 (bs, 2H), 6.43 (d, J=8, 1H), 7.08 (d, J=7, 1H), 7.19 (m,3H), 7.25 (m, 2H), 7.35 (m, 2H), 7.48 (t, J=8, 1H), 7.87 (m, 2H).

[1071]¹³C-NMR (CD₃OD, δ) 33.8, 42.2, 59.1, 61.85, 107.0, 110.7, 125.9,126.7, 128.3, 128.7, 129.2, 138.3, 138.4, 139.3, 140.4, 156.0, 158.3.

[1072] MS (%): 318 (parent+1, 100).

EXAMPLE 1466-{4-[2-(4-(Isoquinolin-1-yl)-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine

[1073] Prepared as in Example 1, using N-isoquinolin-1-yl-piperazine, in30% yield.

[1074]¹H-NMR (CDCl₃, δ): 2.63 (m, 2H), 2.75 (bs, 4H), 2.85 (m, 2H), 3.38(bs, H), 5.95 (bs, 2H), 6.39 (d, J=8, 1H), 7.02 (d, J=7, 1H), 7.31 (m,2H), 7.39 (d, =4, 1H), 7.45 (t, J=8, 1H), 7.60 (t, J=6, 1H), 7.71 (t,J=6, 1H), 7.89 (m, 3H), 8.09 (m, 2H).

[1075] MS (%): 410 (parent+1, 100), 216 (38), 145 (45).

[1076] Anal. (after conversion to the hydrochloride salt) Calc'd. for₂₅H₂₇N₅4HCl2H₂O: C 52.79, H 5.92, N 11.83. Found: C 53.11, H 6.06, N1.53.

1. A compound of the formula

and the pharmaceutically acceptable salts thereof, wherein R¹ and R² areselected, independently, from (C₁-C₆) alkyl, tetrahydronaphthalene andaralkyl, wherein the aryl moiety of said aralkyl is phenyl or naphthyland wherein said (C₁-C₆) alkyl or said tetrahydronaphthalene group orthe aryl ring of said aralkyl group may optionally be substituted withfrom one to three substituents, that are selected, independently, fromhalo, nitro, hydroxy, cyano, amino, (C₁-C₄) alkoxy, and (C₁-C₄)alkylamino; or R¹ and R² form, together with the nitrogen to which theyare attached, a piperazine, piperidine or pyrrolidine ring or anazabicyclic ring containing from 6 to 14 ring members, from 1 to 3 ofwhich are nitrogen and the rest of which are carbon; and wherein saidpiperazine, piperidine and pyrrolidine rings may optionally besubstituted with one or more substituents, preferably with from zero totwo substituent that are selected, independently, from (C₁-C₆) alkyl,amino, (C₁-C₆) alkylamino, [di-(C₁-C₆) alkyll amino, phenyl substituted5 to 6 membered heterocyclic rings containing from 1 to 4 rings nitrogenatoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl,phenylethyl and phenoxycarbonyl, and wherein the phenyl moieties of anyof the foregoing substituents may optionally be substituted with one ormore substituents that are selected, independently, from halo,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, nitro, amino, cyano, CF₃ and OCF₃; n is 0,1or 2; m is 0, 1 , or 2; each R⁸ and each R⁹ is selected, independantly,from (C₁-C₄)alkyl wherein said aryl is selcected from phenyl andnaphthyl; alikyl and phenallyl; X and Y are selected, independently,from methyl, methony hydroxy and hydrogon; and R¹⁰ is (C₁-C₅) alkyl;with the proviso that R¹ is absent when N is zero and R⁹ is absent whenM is zero. or a pharmaceutically acceptable salt of such compound.
 2. Acompound according to claim 1 , wherein NR¹R² is an optionallysubstituted piperidine, piperazine or pyrrolidine ring or one of thefollowing rings: R³ and R⁴ are selected from hydrogen, alkyl, aryl,acyl, aroyl, carbamoyl, carbalkoxy; and R⁵ is selected from hydrogen,alkyl, aryl, and aralkyl.
 3. A compound according to claim 1 whereinNR¹R² is 4-phenoxycarbonylpiperazin-1-yl;4-(4-fluorophenylacetyl)piperazin-1-yl; 4-phenylethylpiperazin-1-yl;4-phenoxymethylcarbonylpiperazin-1-yl;4-phenylaminocarbonyipiperazin-1-yl; 4-benzoylmethylpiperazin-1-yl; or4-benzylcarbonylpiperazin-1-yl.
 4. A compound according to claim 1wherein NR¹R² is a group of the formula

wherein NR³R⁴ is NH₂.
 5. A compound according to claim 1 wherein NR¹R²is a group of the formula

wherein R⁵ is aralkyl and R⁶ is (4-fluoro)phenylacetyl.
 6. A compoundaccording to claim 1 , wherein such compound is selected from:1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-ethanone1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-methoxy-ethanone1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenoxy-ethanone(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-cyclopentyl-methanone1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyI]-ethyI}-piperazin-1-yl)-1-phenyl-ethanol{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine6-{4-[2-(4-Amino-2,6-dimethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine6-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-dimethyl-amine6-[4-(2-Amino-ethyl)-phenyl]-pyridin-2-ylamine6-{4-[2-(8-Aza-spiro[4.5]dec-8-yl)-ethyl]-phenyl}-pyridin-2-ylamine6-{4-[2-(4-isobutyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylicacid p-tolyl-amide6-(4-{2-[4-(3-Phenyl-propyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-chloro-phenyl)-ethanone8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-benzyl-1, 3,8-triaza-spiro[4.5]decane-2, 4-dioneN-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-fluro-phenyl)-acetamide8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-ylamine3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.2.1]oct-8-ylamine2-Amino-1-(4-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-3-phenyl-propan-1-one6-{4-[2-(4-Amino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine6-{4-[2-(4-Benzhydryl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine6-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamineand the pharmaceutically acceptable salts of such compounds.
 7. Apharmaceutical composition for treating or preventing a conditionselected from the group consisting of migraine inflammatory diseases,stroke, acute and chronic pain, hypovolemic shock, traumatic shock,reperfusion injury, Crohn's disease, ulcerative colitis, septic shock,multiple sclerosis, AIDS associated dementia, neurodegenerativediseases, neuron toxicity, Alzheimer's disease, chemical dependenciesand addictions, emesis, epilepsy, anxiety, psychosis, head trauma, adultrespiratory distress syndrome (ARDS), morphine induced tolerance andwithdrawal symptoms, inflammatory bowel disease, osteoarthritis,rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinalcord injury, Huntington's disease, Parkinson's disease, glaucoma,macular degeneration, diabetic neuropathy, diabetic nephropathy andcancer in a mammal, comprising an amount of a compound according toclaim 1 that is effective in treating or preventing such condition and apharmaceutically acceptable carrier.
 8. A method of treating orpreventing a condition selected from the group consisting of migraineinflammatory diseases, stroke, acute and chronic pain, hypovolemicshock, traumatic shock, reperfusion injury, Crohn's disease, ulcerativecolitis, septic shock, multiple sclerosis, AIDS associated dementia,neurodegenerative diseases, neuron toxicity, Alzheimer's disease,chemical dependencies and addictions, emesis, epilepsy, anxiety,psychosis, head trauma, adult respiratory distress syndrome (ARDS),morphine induced tolerance and withdrawal symptoms, inflammatory boweldisease, osteoarthritis, rheumatoid arthritis, ovulation, dilatedcardiomyopathy, acute spinal cord injury, Huntington's disease,Parkinson's disease, glaucoma, macular degeneration, diabeticneuropathy, diabetic nephropathy and cancer in a mammal, comprisingadministering to said mammal an amount of a compound according to claim1 , that is effective in treating or preventing such condition.
 9. Apharmaceutical composition for inhibiting nitric oxide synthase (NOS) ina mammal, according to claim 1 , comprising a NOS inhibiting effectiveamount of a compound according to claim 1 , and a pharmaceuticallyacceptable carrier.
 10. A method of inhibiting NOS in a mammal,comprising administering to said mammal a NOS inhibiting effectiveamount of a compound according to claim 1 .
 11. A pharmaceuticalcomposition for treating or preventing a condition selected from thegroup consisting of migraine, inflammatory diseases, stroke, acute andchronic pain, hypovolemic shock, traumatic shock, reperfusion injury,Crohn's disease, ulcerative colitis, septic shock, multiple sclerosis,AIDS associated dementia, neurodegenerative diseases, neuron toxicity,Alzheimer's disease, chemical dependencies and addictions, emesis,epilepsy, anxiety, psychosis, head trauma, adult respiratory distresssyndrome (ARDS), morphine induced tolerance and withdrawal symptoms,inflammatory bowel disease, osteoarthritis, rheumatoid arthritis,ovulation, dilated cardiomyopathy, acute spinal cord injury,Huntington's disease, Parkinson's disease, glaucoma, maculardegeneration, diabetic neuropathy, diabetic nephropathy and cancer in amammal, comprising a NOS inhibiting effective amount of a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 12. Amethod of treating or preventing a condition selected from the groupconsisting of migraine, inflammatory diseases, stroke, acute and chronicpain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn'sdisease, ulcerative colitis, septic shock, multiple sclerosis, AIDSassociated dementia, neurodegenerative diseases, neuron toxicity,Alzheimer's disease, chemical dependencies and addictions, emesis,epilepsy, anxiety, psychosis, head trauma, adult respiratory distresssyndrome (ARDS), morphine induced tolerance and withdrawal symptoms,inflammatory bowel disease, osteoarthritis, rheumatoid arthritis,ovulation, dilated cardiomyopathy, acute spinal cord injury,Huntington's disease, Parkinson's disease, glaucoma, maculardegeneration, diabetic neuropathy, diabetic nephropathy and cancer in amammal, comprising administering to said mammal a NOS inhibitingeffective amount of a compound according to claim 1 .